Mouse Genome Informatics
hm1
    Apoetm1Unc/Apoetm1Unc
B6.129P2-Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mice maintained on a high fat diet and infected with Leishmania major generate more IL-4 and IL-5 producing CD4+ T cells compared to wild-type mice
• the immune response of mice fed a high fat diet to Leishmania major infection is skewed towards a Th2-type response
• in an adoptive transfer experiment, the proliferation of Tg(TcrLCMV)2Aox CD45.2+ cell in mice fed a high fat diet and receiving then immunized with GP61-80 peptide with CpG is reduced compared to in wild-type mice similarly treated
• dendrictic cells mount reduced IL-12p40 and TNF-alpha responses to stimulation with zymosan, poly(I:C), LPS, imiquimod, and a combination of anti-CD40 antibodies and CpG compared to wild-type mice but similar to wild-type mice fed a high fat diet
• in mice fed a high fat diet, dendritic cell production of IL-12p40, IL-6 and TNF-alpha after 35 to 40 weeks, but not after 6 to 10 weeks, is severely impaired compared to wild-type cells in response to CpG/anti-CD-40 stimulation
• CD8alpha-, but not CD8alpha+, dendritic cells are defective in their ability to produce IL-12p40
• dendritic cells from mice on a high fat diet are severely impaired in their ability to produce Il-12p40, -12p70, -6, and TNF-alpha compared to dendritic cells from wild-type mice on a high fat diet
• however, CD8alpha+ dendritic cells produce normal amounts of Il-12p70 and -12p40
• mice fed a high fat diet and co-stimulated with CpG or LPS have fewer IL-12p40-producing CD8alpha- dendritic cells (4.6+/-1.1%) than wild-type mice fed a high fat diet (15.3+/-2.4%)
• however, the immune responses of bone marrow derived dendritic cells from mice fed a high fat diet or splenic dendritic cells from mice fed a regular diet are normal
• mice maintained on a high fat diet and infected with Leishmania major produce more IL-4 and IL-5 producing CD4+ T cells compared to wild-type mice
• the immune response of mice fed a high fat diet to Leishmania major infection is skewed towards a Th2-type response
• mice maintained on a high fat diet or regular chow and infected with Leishmania major exhibit an increased swelling and parasitic burden at the site of infection (footpad)

homeostasis/metabolism
• plasma leptin levels are low at both 6 and 18 months
• mice have increased levels of circulating oxidized lipids compared to wild-type mice
• mice develop severe cholesterolemia when receiving a high fat diet from 6 to 30 weeks (elevated levels are detected at 6, 15, and 30 weeks)

behavior/neurological
• increased water intake at 18 months
• increased food intake at 12 and 18 months but not earlier
• at 6 months as measured in an elevated plus maze
• mice consume food slower in a new environment than Tg(GFAP-APOE_i4)#Hol Apoetm1Unc/Apoetm1Unc and wild-type mice
• mice require more time to habituate to a novel environment compared to wild-type mice
• mice are less reluctant than wild-type mice to move into an open area
• reduced exploratory behavior in an open field test by 12 months although normal earlier
• exploratory behavior remains constant over several days whereas controls show higher initial exploratory behavior which drops off quickly
• at 14 to 17 months of age, mice perform better than Tg(GFAP-APOE_i4)#Hol Apoetm1Unc/Apoetm1Unc and wild-type mice in a rotating holeboard test
• mice spend more time than Tg(GFAP-APOE_i4)#Hol Apoetm1Unc/Apoetm1Unc in the center of an open field
• 41% increase in foot withdrawal latency from painful thermal stimuli
• 100% slower tail withdrawal latency
• after-discharge duration is significantly prolonged by the sixth trial
• delayed rekindling after 3-4 weeks

hematopoietic system
• mice maintained on a high fat diet and infected with Leishmania major generate more IL-4 and IL-5 producing CD4+ T cells compared to wild-type mice

nervous system
• after-discharge duration is significantly prolonged by the sixth trial
• delayed rekindling after 3-4 weeks
• restraint stress at 6 months results in disproportionately low ACTH levels as compared to plasma corticosterone levels
• very little Schwann cell cytoplasm
• blurring of lipid membrane border between axons and Schwann cells
• synaptophysin levels are somewhat more reduced than in controls after entorhinal cortex lesion
• cross-section of unmyelinated axons is irregular
• very little Schwann cell cytoplasm
• blurring of lipid membrane border between axons and Schwann cells
• reduced number of unmyelinated axons
• ratio of unmyelinated to myelinated axons is reduced

endocrine/exocrine glands
• increased lipid droplets seen at six months
• increased lipid droplets seen at six months
• fter 10 min of restraint stress plasma levels are elevated at six months but not at three months
• elevated adrenal levels at six months but not earlier
• restraint stress at 6 months results in disproportionately low ACTH levels as compared to plasma corticosterone levels

adipose tissue
• decreased interscapular brown fat at 18 but not at 6 months
• epididymal white fat reduced at both 6 and 18 months

cardiovascular system
• cellular composition of lesions is similar among Serpine1-deficient or transgenic, Apoe-deficient genotypes, or Apoe-deficient only mice; at early time points, a greater foam cell content is observed, with more prominent cholesterol clefts and necrotic areas evident with increasing age

integument
• 41% increase in foot withdrawal latency from painful thermal stimuli
• 100% slower tail withdrawal latency


Mouse Genome Informatics
hm2
    Apoetm1Unc/Apoetm1Unc
B6.129P2-Apoetm1Unc/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 35% dead by 18 months

cardiovascular system
• endothelial nitric oxide synthase (eNOS) in mutant aortic wall is distinctly reduced (J:101576)
• Cx43 distribution at cell-cell junction shows significant disruption (J:142083)
• arterioles of the vascular pole show a "foamy" degeneration of smooth muscle cells
• homozygotes fed an atherosclerotic diet develop atherosclerotic alterations in the spiral modiolar artery (SMA)
• in contrast, no such changes are detected in the SMA of homozygotes fed a normal diet
• homozygotes exhibit a 13% increase in aortic pulse-wave velocity (PWV) relative to wild-type mice (428 14.5 cm/s vs 379 10.1 cm/s), indicating increased arterial stiffness and reduced vascular elasticity
• 23% of luminal surface in the aortic arch and thoracic aorta is covered by plaques at 4 months of age (J:60364)
• 61% covered by plaques at 13 months of age (J:60364)
• thickened intima, foam cell accumulation and thin collagen cap (J:60364)
• focal fragmentation of elastic laminae (J:60364)
• advanced atherosclerotic lesions; massive atheromas with abundant cholesterol crystals, neutral lipids, and diminished extracellular matrix in arotic roots and coronary arteries (J:73202)
• regular exercise does not reduce atherosclerotic lesion formation in homozygotes, as shown by a comparable % oil red-O staining of whole aortas from sedentary and exercised mutant mice (J:97385)
• at 24 weeks of age, homozygotes fed a normal diet (but not similarly-fed C57BL/6J control mice) show obvious atherosclerotic lesions in the aortic sinus and ascending aorta (J:101576)
• the number of atherosclerotic lesions in aortic sinus and ascending aorta is significantly increased in homozygotes fed an atherosclerotic diet vs a normal diet (J:101576)
• plaques in the luminal surface of the aorta are significantly larger in atherosclerotic diet homozygotes than in normal diet homozygotes (J:101576)
• intimal lesions are observed in atherosclerotic aortas in mutants (J:105736)
• at 13 months, homozygotes display atherosclerotic lesions extending from the carotid arteries, heart, and aorta down to the renal arteries and the iliac bifurcation (J:108154)
• lesions are most severe in the proximal aorta and at the bifurcation of carotid arteries; the proximal carotid arteries are relatively free of lesions (J:108154)
• major lesions are observed on lesser curvature of aortic arch in males and females with minor lesions found at branches of aortic arch (J:142083)
• lesions comprise around 14-16% of total aortic arch area in male and female mutants (J:142083)
• aortic lesions are observed in aortic sinus at level of aortic valve leaflets; lesions are about 27% of total aortal area (J:142083)
• on a high fat, high cholesterol diet, mutants exhibit moderate to severe aortic and carotid atherosclerosis (J:43846)
• severity of atherosclerosis is 2-fold and 99-fold higher in atherosclerotic diet homozygotes than in normal diet homozygotes and C57BL/6J control mice, respectively (J:101576)
• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
• lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice
• such thrombus-like structures commonly dsiplay a laminated appearance with adjacent foam cells in the mesangium
• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
• vascular stenosis is significantly increased in homozygotes fed an atherosclerotic diet vs a normal diet
• lumen stenosis of the spiral modiolar artery in the cochlea is exacerbated by an atherosclerotic diet relative to a normal diet
• at 13 months, homozygotes show a 23% increase in heart weight relative to wild-type mice (186 7.1 vs. 151 2.5 mg)
• at 13 months, homozygotes show a 59% increase in heart weight-to-body weight ratio relative to wild-type mice
• anesthetized homozygotes show significantly increased transaortic blood velocities relative to wild-type mice with peak aortic velocity at 133.4 7.8 cm/s vs 89.2 5.8 cm/s, and mean aortic velocity at 35.9 2.7 vs 22.0 1.6 cm/s, respectively
• in addition, anesthetized homozygotes show significantly increased transmitral blood velocities relative to wild-type mice with peak mitral velocities at 92 7.2 cm/s vs 47.2 5.3 cm/s, and mean mitral velocities at 20.6 1.7 vs 11.4 1.3 cm/s, respectively
• no significant differences in heart rate, peak aortic acceleration or ejection time are observed in the conscious or anesthetized state, when normalized to body weight
• however, homozygotes show alterations in aortic arch acceleration suggestive of increased peripheral wave reflections
• under anesthesia, homozygotes exhibit elevated flow velocities suggesting elevated cardiac output
• under anesthesia, homozygotes appear to exhibit significantly increased stroke volume
• under anesthesia, homozygotes appear to exhibit significantly reduced peripheral vascular resistance and compliance in the presence of normal blood pressures
• pulse wave velocity is insignificantly elevated at 4 months
• pulse wave velocity significantly elevated at 13 months
• impaired blood-brain barrier and blood-nerve barrier as indicated by extensive extravasation of serum proteins into sciatic nerve, spinal cord and cerebellum and occasional extravasation into cortex and subcortex
• homozygotes fed a normal or atherosclerotic diet show severely impaired endothelium-dependent relaxation to acetylcholine in aortic rings relative to age-matched C57BL/6J control mice
• aortae show macrophage and T cell extravasation within atherosclerotic lesions

muscle
• homozygotes fed a normal or atherosclerotic diet show severely impaired endothelium-dependent relaxation to acetylcholine in aortic rings relative to age-matched C57BL/6J control mice
• relaxation response to acetylcholine in blood vessels is significantly attenuated at 13 months of age
• maximal response to acetylcholine is considerably reduced

homeostasis/metabolism
• lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice
• such thrombus-like structures commonly dsiplay a laminated appearance with adjacent foam cells in the mesangium
• decrease in plasma total homocysteine levels
• decreased HDL/total cholesterol ratio
• decreased HDL/LDL ratio
• increasing with age; 4-fold increase in plasma total cholesterol levels in 10-12 week old mutants and 13-fold increase at 29 weeks (J:73202)
• exercise (15 or 60 min/day swim) causes no significant changes in total cholesterol levels among homozygotes or wild-type mice relative to sedentary, genotype-matched controls (J:97385)
• on a normal diet, homozygotes display significantly increased plasma total cholesterol (TC) levels relative to C57BL/6J control mice (J:101576)
• on an atherosclerotic diet, homozygotes show a further significant increase in plasma TC levels relative to homozygotes on a normal diet (J:101576)
• total serum cholesterol 70 fold higher than controls on a normal diet (J:104609)
• total serum cholesterol 20 fold higher than controls on high fat diet where controls show 4 fold increase over normal diet (J:104609)
• 5 fold increase in total cholesterol at 24 and 36 weeks (J:125978)
• significantly increased relative to wild-type controls at 24 weeks of age; levels in mutants after induction of chronic graft versus host disease (cGVH) to induce systemic lupus erythematosus (SLE) are equivalent to the Apoe-null mice (J:133606)
• on a normal diet, homozygotes display significantly increased plasma LDL cholesterol levels relative to C57BL/6J control mice (J:101576)
• on an atherosclerotic diet, homozygotes show a further significant increase in plasma LDL levels relative to homozygotes on a normal diet (J:101576)
• on a normal diet, homozygotes display significantly increased plasma VLDL cholesterol levels relative to C57BL/6J control mice (J:101576)
• on an atherosclerotic diet, homozygotes show a further significant increase in plasma VLDL cholesterol levels relative to homozygotes on a normal diet (J:101576)
• 2-fold increase in plasma triglyceride levels in 10-12 week old mutants (J:73202)
• on a normal diet, homozygotes display significantly increased plasma triglyceride levels relative to C57BL/6J control mice (J:101576)
• on an atherosclerotic diet, homozygotes show a further significant increase in plasma triglyceride levels relative to homozygotes on a normal diet (J:101576)
• homozygotes develop hyperlipidemia; however, HDL cholesterol levels, body weight and blood glucose remain unchanged relative to C57BL/6J control mice on a normal diet, with no further differences noted on an atheroscletoric diet
• 1 of 11 aged mice on a normal diet develops cerebral xanthoma (J:43846)
• eruptive xanthomas on shoulder and back areas with lipids and extracellular matix as the predominant components (J:73202)
• activity of cholesterol synthesis enzyme HMG-CoA reductase is reduced up to 60% in aging mice compared to 30% in wild-type aging mice

growth/size
• at 13 months, homozygotes show a 22% reduction in body weight relative to wild-type mice (34.5 0.9 vs. 44.5 1.1 g) (J:108154)
• nose to rump length less than controls at both 1 and 3 months
• body weight was less than controls at 3 months but identical at 8 months

hematopoietic system
• at 13 months, awake, unanesthetized homozygotes display slightly but significantly reduced hematocrits ( 11%) relative to wild-type mice at 41.7 1.1% vs 46.6 0.4%; in contrast, systolic blood pressures remain unaffected (140 7.6 mmHg vs 136 7.4 mmHg)
• decreased relative to controls
• with induction of SLE by cGVH, levels are slightly decreased compared to wild-type
• newly formed B cells are significantly increased compared to wild-type
• increased 2-fold compared to wild-type
• increased numbers of cytokine producing T cells
• clusters of CD4+ cells found in fatty streak lesions (J:47027)
• ratio of Th2 to Th1 cells is increased from 4.4 to 11.4 on a normal diet and up to 20.9 on a high cholesterol diet (J:47027)
• spleen cells display polyclonal B cell activation, with increased expression of MHC II, Fas, and CD86 and lower expression of CD21, CD22, and CD23
• increased spleen weight while the thymus weight remains normal
• mutants with cGVH-induced SLE show greatly increased levels compared to wild-type controls or untreated mutants
• IgM response to tetanus toxoid is significantly increased as compared to controls

cellular
• regular exercise fails to reduce endogenous oxidant load and mitochondrial damage in hypercholesterolemic mutant mice
• in contrast, regular exercise results in reduced mitochondrial damage and oxidant load and increased SOD2 and adenine nucleotide translocator activities in normocholesterolemic control mice

hearing/vestibular/ear
• endothelial nitric oxide synthase (eNOS) in mutant cochlea is distinctly reduced
• on an atherosclerotic diet, homozygotes display a sclerosed and atrophic basilar membrane
• at 24 weeks, homozygotes fed a normal diet show almost complete loss of IHCs in the basal turn and some IHC loss in the middle turn
• IHC loss at the base turn is exacerbated by an atherosclerotic diet
• at 24 weeks, homozygotes fed a normal diet show almost complete loss of OHCs in the basal turn and some OHC loss in the middle turn
• OHC loss at the base turn is exacerbated by an atherosclerotic diet
• at 24 weeks, homozygotes fed a normal diet show significant degeneration of the organ of Corti in the basal turn while the middle turn is relatively normal
• degeneration of the organ of Corti is excerbated by an atherosclerotic diet, with complete loss noted in the basal turn in some animals
• on an atherosclerotic diet, homozygotes display a sclerosed and atrophic stria vascularis
• on an atherosclerotic diet, homozygotes display a sclerosed and atrophic tectorial membrane
• at 10 weeks, homozygotes fed a normal diet display higher ABR thresholds than C57BL/6J control mice at all test frequencies, with more hearing loss noted at 32 kHz; by 24 weeks, further hearing loss is detected at all test stimuli levels
• homozygotes fed an atherosclerotic diet show higher ABR thresholds than homozygotes fed a normal diet
• homozygotes fed a normal diet display hearing loss esp. at high frequencies as compared with C57BL/6J control mice
• a high positive correlation between ABR thresholds at 16 and 8 kHz, or click and atherosclerotic lesions, and atherosclerotic plaque area of the aorta, and plasma total choelsterol levels is observed in both normal diet and high-fat diet homozygotes

nervous system
• impaired blood-brain barrier and blood-nerve barrier as indicated by extensive extravasation of serum proteins into sciatic nerve, spinal cord and cerebellum and occasional extravasation into cortex and subcortex
• at 24 weeks, homozygotes fed a normal diet show almost complete loss of IHCs in the basal turn and some IHC loss in the middle turn
• IHC loss at the base turn is exacerbated by an atherosclerotic diet
• at 24 weeks, homozygotes fed a normal diet show almost complete loss of OHCs in the basal turn and some OHC loss in the middle turn
• OHC loss at the base turn is exacerbated by an atherosclerotic diet
• at 24 weeks, homozygotes fed a normal diet show a reduced number of spiral ganglion cells in the basal turn of the cochlea
• loss of ganglion cells is excerbated by an atherosclerotic diet

immune system
• decreased relative to controls
• with induction of SLE by cGVH, levels are slightly decreased compared to wild-type
• newly formed B cells are significantly increased compared to wild-type
• increased 2-fold compared to wild-type
• increased numbers of cytokine producing T cells
• clusters of CD4+ cells found in fatty streak lesions (J:47027)
• ratio of Th2 to Th1 cells is increased from 4.4 to 11.4 on a normal diet and up to 20.9 on a high cholesterol diet (J:47027)
• increased spleen weight while the thymus weight remains normal
• aortae show macrophage and T cell extravasation within atherosclerotic lesions
• spleen cells display polyclonal B cell activation, with increased expression of MHC II, Fas, and CD86 and lower expression of CD21, CD22, and CD23
• decreased antigen specific delayed hypersensitivity response
• mutants with cGVH-induced SLE show greatly increased levels compared to wild-type controls or untreated mutants
• IgM response to tetanus toxoid is significantly increased as compared to controls
• production is reduced when fed a high cholesterol diet
• after induction of cGVH-SLE, IgG and IgM anti-oxidized LDL and anti-cardiolipin antibodies are increased compared to wild-type or Apoe-null controls
• after induction of cGVH-SLE, mice display greatly increased levels of anti-chromatin antibodies compared to wild-type controls or non-cGVH mutants
• after induction of cGVH-SLE, mice display greatly increased levels compared to wild-type controls or non-cGVH-SLE mutants

behavior/neurological
• elevated thigmotaxis in Morris maze tests
• longer latency to find the platform in Morris maze tests
• slow to acquire a preference for the target quadrant and the magnitude of the preference is always less than controls

renal/urinary system
• arterioles of the vascular pole show a "foamy" degeneration of smooth muscle cells
• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
• increased glomerular tuft area
• glomerular cell numbers are increased
• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
• lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice
• such thrombus-like structures commonly dsiplay a laminated appearance with adjacent foam cells in the mesangium
• progressive increase in glomerular matrix, already evident at 24 weeks, associated with accumulation of laminin and collagen IV
• loss of mesangial matrix sometimes at 36 weeks but never at 24 weeks or in controls
• glomerular foam cells in the mesangium, capillary lumina and within the glomerular stalk close to the vascular pole
• lipid deposits in arteriolar walls in the vascular poles
• lipid droplets filling glomerular capillary lumina at 36 weeks in about 50% of mice

liver/biliary system
• no significant change in serum alanine transaminase with high fat diet as is seen in controls (marker for liver damage)
• hepatic uptake of LDL is increased two fold

vision/eye
• perinuclear vacuolation on a high cholesterol diet
• cell numbers reduced
• cell numbers reduced
• implicit times increased for a and b waves of dark adapted electroretinogram (J:70245)
• wave amplitudes attenuated for a and b waves of dark adapted electroretinogram (J:70245)

taste/olfaction
• preference for plain water over 0.1% iso-amyl alcohol moderate compared to the strong preference shown by controls
• slower than control to find buried food pellet although found pellets visually more rapidly
• latency to taste vanillin-cued quinine significantly increased only at day 5

skeleton
• higher bone mineralization density in vertebral bodies
• increased bone volume to tissue volume ratio
• in vertebral bodies and tibia
• increased number of trabeculae
• increased rate of bone formation

respiratory system
• less surface area to volume
• fewer but larger alveoli at 3 months of age
• percent increase in hysteresivity with age greater than in controls
• lung volume similar to controls at 3 months but 2.5 fold greater at 8 months of age
• resistance to airflow greater than controls at 3 months but not at 8 months of age
• dynamic and static compliance greater than controls at 8 months of age

integument
• progressive skin lesions, mainly seen as eruptive xanthomas on shoulder and back areas with lipids and extracellular matix as the predominant components


Mouse Genome Informatics
hm3
    Apoetm1Unc/Apoetm1Unc
B6.Cg-Apoetm1Unc Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mice display greatly increased levels compared to wild-type controls or Apoe-null mice
• mice display greatly increased levels compared to wild-type controls or Apoe-null mice
• mice display greatly increased levels compared to wild-type controls or Apoe-null mice

homeostasis/metabolism
• significantly increased relative to wild-type controls or Fas-single mutants at 24 weeks of age; levels are higher than that of B6.129P2-Apoetm1Unc

cardiovascular system
• modest increase in total area of lipid deposits in aorta compared to Apoe-null mice

hematopoietic system
• mice display greatly increased levels compared to wild-type controls or Apoe-null mice


Mouse Genome Informatics
hm4
    Apoetm1Unc/Apoetm1Unc
either: B6.129P2-Apoetm1Unc/J or (involves: 129P2/OlaHsd * C57BL/6J * ICR)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• no alterations in passive avoidance learning are observed; coordination levels measured in rotorod tests are similar to wild-type (J:100975)
• 6-month old female mice show subtle learning impairment in water maze task compared to transgenic mutants; 6-month old males show significantly decreased learning ability in the Morris water maze test
• mice have fewer rearing events and shorter rearing times than wild-type controls

nervous system
N
• upon 18 mg/kg kainic acid injection, significant loss of neocortical synaptophysin-positive presynaptic terminals and disruption of hippocampal axons are observed, similar to wild-type (J:55835)
• mice show significant loss of synaptophysin-positive presynaptic terminals and neuronal dendrites of the neocortex and hippocampus with age (7-9 months compared to 3-4 months), similar to wild-type (J:55835)
• mice exhibit age-dependent loss of synaptophysin-reactive terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, similar to wild-type (J:100975)


Mouse Genome Informatics
hm5
    Apoetm1Unc/Apoetm1Unc
involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• in the elevated-plus maze, mice show increased anxiety with reduced time and distance moved in the open arms; mice have significantly lower number of open-arm entries than wild-type
• effect is age-dependent; phenotype is present in older mice, but not in young 2-4 month-old mice
• response is higher in mice at 6 months of age compared to wild-type

homeostasis/metabolism
• all males have higher plasma concentrations than wild-type after behavioral testing
• circulating VLDL/LDL cholesterol levels are increased compared to in Apobec1tm1Chan homozygotes and wild-type mice
• when fed a chow or Western-type diet for 2 weeks, mice exhibit increased serum cholesterol compared with Apobec1tm1Chan homozygotes and wild-type mice
• compared to in Tg(Eno2-APP751)10Cord Apoetm1Unc/Apoetm1Unc mice

nervous system
• compared to in Tg(Eno2-APP751)10Cord Apoetm1Unc/Apoetm1Unc mice
• mutants have lower levels of MAP 2-positive neuronal dendrites than wild-type; at 3 months, levels are similar in mutants and controls

cardiovascular system
• atherosclerotic lesions begin to form in the left common carotid by 2 weeks after partial ligation of the left common carotid
• atherosclerotic lesion development is well advanced by 4-6 weeks after partial ligation of the left common carotid
• bone marrow transplanted into Apoa1tm1Unc homozygotes confer susceptibility to atherosclerosis
• impaired vasodilation induced by sodium nitroprusside 7 days after partial ligation of the left common carotid

muscle
• impaired vasodilation induced by sodium nitroprusside 7 days after partial ligation of the left common carotid


Mouse Genome Informatics
hm6
    Apoetm1Unc/Apoetm1Unc
involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Morphology of aortic lesions in Apoetm1Unc/Apoetm1Unc and Apoetm1Unc/Apoetm1Unc Ttpatm1Far/Ttpatm1Far mice

cardiovascular system
• most severe in the aortic arch region


Mouse Genome Informatics
hm7
    Apoetm1Unc/Apoetm1Unc
involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• fatty streaks with foam cells are found in the proximal aorta of 3-8 month old mice fed normal chow (J:16573)
• the foam cells are often adjacent to valve attachment sites and can form multi-layers (J:16573)
• lesions get bigger with age and near total occlusion at the entrance of a coronary artery can be observed at 8 months of age (J:16573)
• 75% of mice develop lesions in the aortic arch with most females and some males having calcification within the lesions (J:40136)
• aortic cartilaginous metaplasia is noted in the most severely affected mice (J:40136)
• greater than in wild-type (J:80689)

homeostasis/metabolism
• mean HDL levels (33 mg/dl) are 45% of that found in controls
• mean total cholesterol levels are elevated about 5-fold over wild-type to 434 mg/dl (J:16573)
• total cholesterol levels are about 4-fold higher than controls with a mean of 379 mg/dl (J:40136)
• relative to wild-type (J:80689)
• mice have elevated levels of LDL in the blood
• the majority of lipoprotein particles in the blood are in the VLDL size range
• circulating triglyceride levels are 123 mg/dl compared to 73 mg/dl in controls (J:16573)
• relative to wild-type (J:80689)
• relative to wild-type
• amount of PGE2 in aortas is 4X higher than in controls
• PGE2 level doubles on a high fat diet

nervous system
• elevated cholesterol in the exofacial leaflet of the synaptic plasma membrane but not so high as for Ldlr deficient mice
• cholesterol levels in the cytofacial leaflet are reduced
• astrocytes secrete less phospholipids or free cholesterol compared to wild-type astrocytes

immune system
• isolated small foci of mononuclear cells are present in lung after 6 weeks of high-fat feeding

respiratory system
• isolated small foci of mononuclear cells are present in lung after 6 weeks of high-fat feeding

Mouse Models of Human Disease
OMIM IDRef(s)
Apolipoprotein E; APOE 107741 J:16573


Mouse Genome Informatics
hm8
    Apoetm1Unc/Apoetm1Unc
involves: 129P2/OlaHsd * C57BL/6 * DBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increase in APOB-48
• the HDL phospholipid fraction is enriched in 16:0 and 18:0 species and contains less 20:4 and 22:6 species compared to Ldlrtm1Her single mutants
• increase in the APOB lipoprotein cholesterol level compared to wild-type controls
• there is a 2.3 fold increase in the ratio of saturated + monounsaturated/polyunsaturated cholesterol ester fatty acid species compared to Ldlrtm1Her single mutants
• the ratio of saturated + monounsaturated/polyunsaturated cholesterol ester fatty acid species in the LDL fraction is significantly increased compared to Ldlrtm1Her single mutants
• about a 50% decrease in HDL compared to controls
• increased total cholesterol and esterfied cholesterol levels in the plasma


Mouse Genome Informatics
hm9
    Apoetm1Unc/Apoetm1Unc
involves: 129P2/OlaHsd * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• lesions are observed in aortas of nontransgenic mice


Mouse Genome Informatics
hm10
    Apoetm1Unc/Apoetm1Unc
Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
adipose tissue

hematopoietic system

homeostasis/metabolism
WTSI (J:175295)
EuPh (J:165965)
WTSI (J:175295)
EuPh (J:165965)
WTSI (J:175295)
EuPh (J:165965)

immune system

growth/size


Mouse Genome Informatics
ht11
    Apoetm1Unc/Apoe+
involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• circulating triglyceride levels are 39% higher than in wild-type controls


Mouse Genome Informatics
ht12
    Apoetm1Unc/Apoe+
Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system

immune system


Mouse Genome Informatics
ht13
    Apoeshl/Apoetm1Unc
involves: 129P2/OlaHsd * KOR
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• in all mice


Mouse Genome Informatics
cn14
    Apoetm1Unc/Apoetm1Unc
Gja5tm1Mchn/Gja5tm1Mchn
Tg(TIE2-lacZ)182Sato/0

involves: 129P2/OlaHsd * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• mice exhibit normal mean arterial pressure, heart rate, and endothelium-dependent vasomotor responses to KCl and norepinephrine (J:162224)
• whether fed a high-fat or standard diet, mice exhibit increased lipid staining in the thoracoabdominal aortas compared with Apoetm1Unc homozygotes
• whether fed a high-fat or standard diet, mice exhibit accelerated atherosclerosis compared with Apoetm1Unc homozygotes

immune system
• LPS-treated mice exhibit increased inflammatory cell recruitment, mostly neutrophils, into the alveolar spaces compared with similarly treated Apoetm1Unc homozygotes
• LPS-treated mice exhibit increased inflammatory cell recruitment, mostly neutrophils, into the alveolar spaces compared with similarly treated Apoetm1Unc homozygotes

respiratory system
• LPS-treated mice exhibit increased inflammatory cell recruitment, mostly neutrophils, into the alveolar spaces compared with similarly treated Apoetm1Unc homozygotes

hematopoietic system
• LPS-treated mice exhibit increased inflammatory cell recruitment, mostly neutrophils, into the alveolar spaces compared with similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cn15
    Apoetm1Unc/Apoetm1Unc
Klf15tm2Jain/Klf15tm2Jain
Tg(Tagln-cre)1Jjl/0

involves: 129P2/OlaHsd * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
N
• mice fed a high fat diet exhibit the same circulating levels of cholesterol and triglycerides as in Apoetm1Unc homozygotes (J:203920)

immune system
• increased macrophage in the aortic wall and atherosclerotic lesions of mice fed a high fat diet with Apoetm1Unc homozygotes
• increased macrophage in the aortic wall and atherosclerotic lesions of mice fed a high fat diet with Apoetm1Unc homozygotes

cardiovascular system
• in mice fed a high fat diet compared with Apoetm1Unc homozygotes
• decreased vascular smooth muscle cells in the aortic wall and atherosclerotic lesions of mice fed a high fat diet with Apoetm1Unc homozygotes
• increased macrophage in the aortic wall and atherosclerotic lesions of mice fed a high fat diet with Apoetm1Unc homozygotes

muscle
• decreased vascular smooth muscle cells in the aortic wall and atherosclerotic lesions of mice fed a high fat diet with Apoetm1Unc homozygotes

hematopoietic system
• increased macrophage in the aortic wall and atherosclerotic lesions of mice fed a high fat diet with Apoetm1Unc homozygotes


Mouse Genome Informatics
cx16
    Apoetm1Unc/Apoetm1Unc
Thbdtm1.1(THBD)Sltz/Thbdtm1.1(THBD)Sltz

B6.129(FVB)-Thbdtm1.1(THBD)Sltz Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
N
• mice fed a high fat diet exhibit the same increase in total cholesterol, atherosclerotic lesion area and time to occlusion of the carotid artery following photochemical injury as Apoetm1Unc homozygotes (J:191461)
• mice fed a high fat diet exhibit decreased amount of circulating activated protein C compared with Apoetm1Unc homozygotes


Mouse Genome Informatics
cx17
    Apoetm1Unc/Apoetm1Unc
Cdkn1atm1Tyj/Cdkn1atm1Tyj

B6.129-Apoetm1Unc Cdkn1atm1Tyj
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• angiotensin II-treated mice exhibit less of an increase in mortality compared with similarly treated Apoetm1Unc homozygotes

cardiovascular system
• angiotensin II-treated mice exhibit a smaller increase in plaque area, plaque grade, aortic aneurysms, atheroma, and mortality but an increase in proliferation of vascular smooth muscle cells compared with similarly treated Apoetm1Unc homozygotes
• treatment with angiotensin II induces less vascular smooth muscle cell senescence and more proliferation compared to in similarly treated Apoetm1Unc homozygotes

homeostasis/metabolism
• angiotensin II-treated mice exhibit a smaller increase in plaque area, plaque grade, aortic aneurysms, atheroma, and mortality but an increase in proliferation and decrease in senescence of vascular smooth muscle cells compared with similarly treated Apoetm1Unc homozygotes

cellular
• treatment with angiotensin II induces less vascular smooth muscle cell senescence compared to in similarly treated Apoetm1Unc homozygotes

muscle
• treatment with angiotensin II induces less vascular smooth muscle cell senescence and more proliferation compared to in similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cx18
    Apoetm1Unc/Apoetm1Unc
Cx3cl1tm1Sgs/Cx3cl1tm1Sgs

B6.129-Apoetm1Unc Cx3cl1tm1Sgs
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• brachiocephalic artery lesion area is reduced by about 85% at 200 um and 400 um but not at 600 um from its branching site into the carotid and subclavian arteries in female double homozygotes compared to Apoe single homozygotes
• in male double homozygotes brachiocephalic artery lesion area is reduced by 82% at 200 um, 58% at 400 um, and 59% at 600 um
• aortic root lesion area is reduced by about 30% in double homozygous females at 12 weeks of age but not in males at 12 weeks or in either sex at 16 weeks
• lesions are less advanced than in Apoe single homozygotes and are composed almost entirely of foam cells

immune system
• atherosclerotic lesions are composed almost entirely of foam cells
• macrophage accumulation is reduced by 80% in the brachiocephalic artery at 200 um from its branching site into the carotid and subclavian arteries

hematopoietic system
• atherosclerotic lesions are composed almost entirely of foam cells
• macrophage accumulation is reduced by 80% in the brachiocephalic artery at 200 um from its branching site into the carotid and subclavian arteries

cellular
• atherosclerotic lesions are composed almost entirely of foam cells
• macrophage accumulation is reduced by 80% in the brachiocephalic artery at 200 um from its branching site into the carotid and subclavian arteries


Mouse Genome Informatics
cx19
    Apoetm1Unc/Apoetm1Unc
Cx3cr1tm1Zm/Cx3cr1tm1Zm

B6.129-Apoetm1Unc Cx3cr1tm1Zm
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• lesion area in the aorta and aortic sinus is decreased by about 50% compared to mice homozygous for the Apoe allele only; however the accumulation of smooth muscle cells and collagen within the plaque is similar to wild-type
• a 50% reduction is seen in the aortic sinus area containing monocyte-macrophage markers


Mouse Genome Informatics
cx20
    Apoetm1Unc/Apoetm1Unc
Cx3cr1tm1Zm/Cx3cr1+

B6.129-Apoetm1Unc Cx3cr1tm1Zm
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• lesion area in the thoracic aorta is decreased by about 50% compared to mice homozygous for the Apoe allele only


Mouse Genome Informatics
cx21
    Apoetm1Unc/Apoetm1Unc
Ifngtm1Ts/Ifngtm1Ts

B6.129-Apoetm1Unc Ifngtm1Ts
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• about 50% of mice infused with angiotensin-II die within 2 to 10 days due to rupture of the abdominal aorta compared to 0 deaths of mutant mice wild-type for Ifng

cardiovascular system
• about 50% of mice infused with 1000 ng/kg*min angiotensin-II die within 2 to 10 days due to rupture of the abdominal aorta compared to 0 deaths of mutant mice wild-type for Ifng
• increase in the incidence of abdominal aorta aneurysyms in in mice infused with 500 ng/kg*min angiotensin-II compared to mutant mice wild-type for Ifng
• increase in the suprarenal aortic diameter in mice infused with 500 ng/kg*min angiotensin-II compared to mutant mice wild-type for Ifng

growth/size
• compared to mutant mice wild-type for Ifng


Mouse Genome Informatics
cx22
    Apoetm1Unc/Apoetm1Unc
Pecam1Gt(OST16303)Lex/Pecam1Gt(OST16303)Lex

B6.129-Apoetm1Unc Pecam1Gt(OST16303)Lex
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• Cx43 distribution at cell-cell junction shows less disruption than in single Apoe-deficient mice
• major lesions are observed on lesser curvature of aortic arch in males and females with minor lesions found at branches of aortic arch
• lesions comprise around 14-16% of total aortic arch area in male and female mutants
• aortic lesions are observed in aortic sinus at level of aortic valve leaflets; lesions are about 27% of total aortal area

homeostasis/metabolism
N
• cholesterol levels of double mutants on a Western or normal chow diet are not significantly different from diet-matched Apoe-null animals (J:142083)


Mouse Genome Informatics
cx23
    Apoetm1Unc/Apoetm1Unc
Cxcl10tm1Adl/Cxcl10tm1Adl

B6.129-Cxcl10tm1Adl Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• increased incidence of death due to ruptured abdominal aorta aneurysyms following angiotensin-II infusion compared to mutant mice wild-type for Cxcl10

cardiovascular system
• display more severe morphological changes following angiotensin-II infusion compared to mutant mice wild-type for Cxcl10
• increase in the suprarenal aortic diameter and suprarenal/thoracic to infrarenal aortic area ratiosin mice infused with angiotensin-II compared to mutant mice wild-type for Cxcl10
• large aneurysms with spiral dissections are seen following angiotensin-II infusion
• increase in the incidence of grade III aneurysms following angiotensin-II infusion compared to mutant mice wild-type for Cxcl10
• decrease in CD4+ T cell accumulation in angiotensin-II induced aneurysms
• increased incidence of death due to ruptured abdominal aorta aneurysyms following angiotensin-II infusion compared to mutant mice wild-type for Cxcl10
• seen following angiotensin-II infusion
• decrease in lesion size in the angiotensin-II induced model compared to mutant mice wild-type for Cxcl10
• seen following angiotensin-II infusion

immune system
• decrease in macrophage accumulation in the arterial wall in angiotensin-II treated mice
• decrease in CD4+ T cell accumulation in angiotensin-II induced aneurysms

hematopoietic system
• decrease in macrophage accumulation in the arterial wall in angiotensin-II treated mice
• decrease in CD4+ T cell accumulation in angiotensin-II induced aneurysms

cellular
• decrease in macrophage accumulation in the arterial wall in angiotensin-II treated mice


Mouse Genome Informatics
cx24
    Apoetm1Unc/Apoetm1Unc
Hsd11b1tm1Lex/Hsd11b1tm1Lex

B6.129-Hsd11b1tm1Lex Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Decreased aortic root atherosclerosis susceptibility in Apoetm1Unc/Apoetm1Unc Hsd11b1tm1Lex/Hsd11b1tm1Lex mice

immune system
N
• mice fed a high fat diet and subjected to intraperitoneal thioglycollate challenge exhibit normal inflammatory cell migration (J:199430)
• foam cells from mice fed a high fat diet exhibit reduced cholesterol content compared with control cells
• in atherosclerotic lesions of mice fed a high fat diet
• peritoneal foam cells treated with oxidized LDL exhibit reduced secretion of G-CSF, KC, MCP-1 and TNFalpha compared with control cells
• in peritoneal foam cells treated with oxidized LDL

homeostasis/metabolism
• in mice fed a high fat diet as in Apoetm1Unc homozygotes
• decreased total, 7-ketocholesterol and 7beta-hydroxycholesterol levels in the aorta of mice fed a high fat diet compared with similarly treated Apoetm1Unc homozygotes
• foam cells from mice fed a high fat diet exhibit reduced cholesterol content compared with control cells

cardiovascular system
N
• mice fed a high fat diet exhibit normal blood pressure (J:199430)
• decreased total, 7-ketocholesterol and 7beta-hydroxycholesterol levels in the aorta of mice fed a high fat diet compared with similarly treated Apoetm1Unc homozygotes
• foam cells from mice fed a high fat diet exhibit reduced cholesterol content compared with control cells

behavior/neurological
N
• mice fed a high fat diet exhibit normal behavior (J:199430)

growth/size
N
• mice fed a high fat diet exhibit normal weight gain (J:199430)

hematopoietic system
• foam cells from mice fed a high fat diet exhibit reduced cholesterol content compared with control cells
• in atherosclerotic lesions of mice fed a high fat diet
• bone marrow-derived stem cells transferred into Apoetm1Unc recipient fed a high fat diet results in decreased atherosclerosis in whole thoracic aorta and descending aorta

cellular
• foam cells from mice fed a high fat diet exhibit reduced cholesterol content compared with control cells


Mouse Genome Informatics
cx25
    Apoetm1Unc/Apoetm1Unc
Il1r1tm1Imx/Il1r1tm1Imx

B6.129-Il1r1tm1Imx Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• when fed a Western diet with high cholate, but not when fed standard chow or a Western diet
• mice receiving Apoetm1Unc bone marrow develop 1.9-fold smaller lesions compared with similarly treated Apoetm1Unc homozygotes
• when fed either a Western diet with high cholate, mice exhibit a greater active pressure-diameter response compared with similarly treated Apoetm1Unc homozygotes
• when fed either a Western diet with high cholate, mice exhibit greater constriction in response to sensitivity to L-NAME treatment compared with similarly treated Apoetm1Unc homozygotes
• when fed either a Western diet or a Western diet with high cholate, mice exhibit greater vasodilator sensitivity to acetyl choline compared with similarly treated Apoetm1Unc homozygotes
• when fed either a Western diet or a Western diet with high cholate compared with similarly treated Apoetm1Unc homozygotes

homeostasis/metabolism
• when fed either a Western diet compared with similarly treated Apoetm1Unc homozygotes

immune system
• when fed either a Western diet compared with similarly treated Apoetm1Unc homozygotes

muscle
• when fed either a Western diet with high cholate, mice exhibit greater constriction in response to sensitivity to L-NAME treatment compared with similarly treated Apoetm1Unc homozygotes
• when fed either a Western diet or a Western diet with high cholate, mice exhibit greater vasodilator sensitivity to acetyl choline compared with similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cx26
    Apoetm1Unc/Apoetm1Unc
Nceh1tm1Ishi/Nceh1tm1Ishi

B6.129-Nceh1tm1Ishi Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• free cholesterol levels are increased 1.5-fold and 1.3-fold for males and females, respectively, compared to in Apoetm1Unc homozygotes
• cholesterol esters are increased 2-fold and 1.3-fold in males and females, respectively, compared to in Apoetm1Unc homozygotes

cardiovascular system
• atherosclerotic lesions are increased compared to in Apoetm1Unc homozygotes (2.2-fold for males and 2.3-fold in females at 17 weeks, 1.7-fold in males and 2.4-fold for females at 21 weeks)


Mouse Genome Informatics
cx27
    Apoetm1Unc/Apoetm1Unc
Nos3tm1Plh/Nos3tm1Plh

B6.129-Nos3tm1Plh Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• 3 of 12 mice fed a Western type diet for 16 weeks developed atherosclerotic suprarenal abdominal aortic aneurysms that are not seen in Apoe single mutants
• 2 of 12 mice fed a Western type diet for 16 weeks developed acute Stanford type B aortic dissections that are not seen in Apoe single mutants
• increase in lesion area relative to Apoe single mutants when fed a Western type diet
• unlike in Apoe single mutants no difference in lesion area is seen at 4 months of age in double mutants fed a Western type diet
• all mice show distal coronary arteriosclerosis associated with perivascular and endomyocardial fibrosis and endomyocardial scars consistent with nontransmural infarction
• thickening of the interventricular septum is seen in double mutants fed a Western type diet for 16 weeks
• 2 of 10 mice fed a Western type diet for 16 weeks displayed massive dilation of the left ventricle
• thickening of the posterior wall is seen in double mutants fed a Western type diet for 16 weeks
• all mice show distal coronary arteriosclerosis associated with perivascular and endomyocardial fibrosis and endomyocardial scars consistent with nontransmural infarction
• decrease in fractional shortening in double mutants fed a Western type diet for 16 weeks
• increased relative to wild-type controls and Apoe single mutants but similar to Nos3 single mutants

muscle
• decrease in fractional shortening in double mutants fed a Western type diet for 16 weeks

homeostasis/metabolism
• all mice show distal coronary arteriosclerosis associated with perivascular and endomyocardial fibrosis and endomyocardial scars consistent with nontransmural infarction


Mouse Genome Informatics
cx28
    Apoetm1Unc/Apoetm1Unc
Serpine1tm1Mlg/Serpine1tm1Mlg

B6.129-Serpine1tm1Mlg Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• when fed a high fat Western diet for 6-30 weeks, mice develop atherosclerotic aortic lesions of the intimal and medial areas; incidence and severity are similar for Serpine1-deficient or transgenic Apoe-deficient genotypes
• lesions are somewhat larger than those observed on the Ldlr-deficient background
• cellular composition of lesions is similar among Serpine-deficient or transgenic, Apoe-deficient genotypes, or Apoe-deficient only mice; at early time points, a greater foam cell content is observed, with more prominent cholesterol clefts and necrotic areas evident with increasing age
• fibrin deposition is not significantly different among Serpine-deficient or transgenic, Apoe-deficient genotypes, or Apoe-deficient only mice

homeostasis/metabolism
• mice develop severe cholesterolemia when receiving a high fat diet from 6 to 30 weeks (elevated levels are detected at 6, 15, and 30 weeks)


Mouse Genome Informatics
cx29
    Apoetm1Unc/Apoetm1Unc
Cd44tm1Mak/Cd44tm1Mak

B6.129P2-Cd44tm1Mak Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• reduced lesion area in the aortic root and thoracic abdominal aorta in a gene dosage-dependent manner
• normal plasma cholesterol levels


Mouse Genome Informatics
cx30
    Apoetm1Unc/Apoetm1Unc
Cd44tm1Mak/Cd44+

B6.129P2-Cd44tm1Mak Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• reduced lesion area in the thoracic abdominal aorta
• normal plasma cholesterol levels


Mouse Genome Informatics
cx31
    Apoetm1Unc/Apoetm1Unc
Nos3tm1Unc/Nos3tm1Unc

B6.129P2-Nos3tm1Unc Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• microaneurysmal dilations in 20% of males
• sometimes involving coronary arteries
• plaques larger at 4 months than in Apoe homozygotes, by 182% for males and 165% for females
• plaques in descending aorta in 90% of males as opposed to 20% of Apoe males
• about 20mm higher than in Apoe homozygotes

renal/urinary system
• 15% of glomeruli with large lipid deposits in foam cells filling the glomeruli
• glomerular injury progresses to dystrophic calcification and glomerular loss
• 15% lower than in Apoe homozygotes

homeostasis/metabolism
• 66% higher than controls


Mouse Genome Informatics
cx32
    Apoetm1Unc/Apoetm1Unc
Ccr2tm1Ifc/Ccr2tm1Ifc

B6.Cg-Apoetm1Unc Ccr2tm1Ifc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• mice fed a high fat diet exhibit decreased lesion size and macrophage accumulation compared to in Apoetm1Unc homozygotes

hematopoietic system
• mice fed a high fat diet exhibit decreased circulating monocyte numbers compared to in Apoetm1Unc homozygotes

immune system
• mice fed a high fat diet exhibit decreased circulating monocyte numbers compared to in Apoetm1Unc homozygotes


Mouse Genome Informatics
cx33
    Apoetm1Unc/Apoetm1Unc
Ccr2tm1Ifc/Ccr2tm1Ifc
Cx3cl1tm1Lira/Cx3cl1tm1Lira

B6.Cg-Apoetm1Unc Cx3cl1tm1Lira Ccr2tm1Ifc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• mice fed a high fat diet exhibit decreased lesion size and macrophage accumulation compared to in Apoetm1Unc homozygotes and Apoetm1Unc Ccr2tm1Ifc homozygotes

hematopoietic system
• mice fed a high fat diet exhibit decreased circulating monocyte numbers compared to in Apoetm1Unc homozygotes
• however, levels are the same as in Apoetm1Unc Ccr2tm1Ifc homozygotes

immune system
• mice fed a high fat diet exhibit decreased circulating monocyte numbers compared to in Apoetm1Unc homozygotes
• however, levels are the same as in Apoetm1Unc Ccr2tm1Ifc homozygotes


Mouse Genome Informatics
cx34
    Apoetm1Unc/Apoetm1Unc
Faslpr/Faslpr

B6.Cg-Apoetm1Unc Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
N
• at 5 months, there are no significant differences in most leukocyte subsets (NK-cells, monocytes/macrophages, and neutrophils) compared to controls (J:121671)
• numbers of circulating cells are significantly reduced
• numbers of circulating cells are significantly reduced comparted to Apoe-wt, Fas-homozygous mice at 5 months
• significantly enlarged compared to Apoe-null, Fas-heterozygous mice or Apoe-wt, Fas-homozygous mice at 5 months
• serum levels of IgG are significantly higher than in Apoe-null and Apoe-null, Fas-heterozygous mice at 6 weeks and at 5 months

immune system
• numbers of circulating cells are significantly reduced
• numbers of circulating cells are significantly reduced comparted to Apoe-wt, Fas-homozygous mice at 5 months
• significantly enlarged compared to Apoe-null, Fas-heterozygous mice or Apoe-wt, Fas-homozygous mice at 5 months
• serum levels of IgG are significantly higher than in Apoe-null and Apoe-null, Fas-heterozygous mice at 6 weeks and at 5 months
• serum antibodies against oxidized phospholipid (OxPL) are decreased compared to Apoe-wt, Fas-homozygous and Apoe-null, Fas-wt controls
• levels of IgG anti-cardiolipin antibodies are increased at 5 months relative to controls
• levels of IgG anti-POVPC and anti-PGPC autoantibodies are significantly higher than in controls at 5 months; IgM anti-POVPC levels are increased also
• serum levels of IgG anti-dsDNA antibodies are significantly higher than in Apoe-null, Fas-wt controls and Apoe-null, Fas-heterozygous mice at 6 weeks and at 5 months
• renal damage is observed, with IgG and C3 deposits present in the mesangium and peripheral capillary loops

renal/urinary system
• at 5 months, renal sections show an increase in apoptotic cells
• increased apoptotic cells are seen in renal tubules at 5 months
• proteinuria is increased compared to Fas-homozygous controls; proteinuria is not evident at 1 month of age
• renal damage is observed, with IgG and C3 deposits present in the mesangium and peripheral capillary loops
• proliferation of glomerular cells and lobule formation are observed
• glomerular tuft areas are enlarged compared to controls

cardiovascular system
• IgG deposition in thickened aortic intimas is seen at 5 months, but is not observed in controls; neglible complement C3 deposition is observed in double homozygotes
• increased lesion area at aortic valves in mice on a normal chow diet compared to Apoe-null, Fas-wt controls
• increase in apoptotic cells in vessel walls of heart (in vascular lesions) is observed at 5 months relative to controls

limbs/digits/tail
• femoral BMD in females is lower than in Apoe-null, Fas-wt controls at 5 months and at 9 months

skeleton
• femoral BMD in females is lower than in Apoe-null, Fas-wt controls at 5 months and at 9 months
• at 5 months, vertebrae BMD trends to lower values than controls; at 9 months, BMD is significantly lower
• all limbs of female mutants have lower bone mineral densities (BMD) than male mutants at 5 months of age; ostopenia is similar to Apoe-wt, Fas-null mice at 5 months
• femoral BMD is lower in females than controls at 5 months and 9 months; vertebrae BMD shows a similar trend at 5 months and is lower at 9 months
• at 9 months, a progressive decrease in trabecular bones (BV/TV, connectivity density, trabecular number, trabecular thickness) is observed in females compared to female Apoe-null, Fas-wt controls

homeostasis/metabolism
• total serum cholesterol and unesterified cholesterol levels are lower than Apoe-null, Fas-wt controls
• proteinuria is increased compared to Fas-homozygous controls; proteinuria is not evident at 1 month of age

cellular
• at 5 months, renal sections show an increase in apoptotic cells
• increased apoptotic cells are seen in renal tubules at 5 months

endocrine/exocrine glands


Mouse Genome Informatics
cx35
    Apoetm1Unc/Apoetm1Unc
Pik3cgtm1Dwu/Pik3cgtm1Dwu

B6.Cg-Apoetm1Unc Pik3cgtm1Dwu
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• atherosclerotic lesions are reduced 52% at 35 weeks, 32% at 53 weeks, and 36% at 60 weeks compared to in Apoetm1Unc homozygotes

homeostasis/metabolism
• total and non-HDL cholesterol after 60 weeks compared to in Apoetm1Unc homozygotes


Mouse Genome Informatics
cx36
    Apoetm1Unc/Apoetm1Unc
Tg(CMV-Serpine1)1Dgi/0

B6.Cg-Apoetm1Unc Tg(CMV-Serpine1)1Dgi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• when fed a high fat Western diet for 6-30 weeks, mice develop atherosclerotic aortic lesions of the intimal and medial areas; incidence and severity are similar for Serpine1-deficient or transgenic Apoe-deficient genotypes
• lesions are somewhat larger than those observed on the Ldlr-deficient background
• cellular composition of lesions is similar among all Serpine1-deficient or transgenic, Apoe-deficient genotypes, or Apoe-deficient only mice; at early time points, a greater foam cell content is observed, with more prominent cholesterol clefts and necrotic areas evident with increasing age

homeostasis/metabolism
• mice develop severe cholesterolemia when receiving a high fat diet from 6 to 30 weeks (elevated levels are detected at 6, 15, and 30 weeks)


Mouse Genome Informatics
cx37
    Apoetm1Unc/Apoetm1Unc
Tg(GFAP-APOE_i3)37Hol/0

B6.Cg-Apoetm1Unc Tg(GFAP-APOE_i3)37Hol
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• mice exhibit increased protected risk assessment behaviors in an elevated plus maze compared to wild-type mice
• mice consume food slower in a new environment than Tg(GFAP-APOE_i4)#Hol Apoetm1Unc/Apoetm1Unc and wild-type mice
• mice require more time to habituate to a novel environment compared to wild-type mice
• mice are less reluctant than wild-type mice to move into an open area
• at 14 to 17 months of age, mice perform better than Tg(GFAP-APOE_i4)#Hol Apoetm1Unc/Apoetm1Unc and wild-type mice in a rotating holeboard test
• compared to wild-type mice
• mice spend less time than wild-type mice in the center of an open field
• mice exhibit increased numbers of fine movement (not related to ambulation) compared to wild-type mice


Mouse Genome Informatics
cx38
    Apoetm1Unc/Apoetm1Unc
Tg(GFAP-APOE_i4)#Hol/0

B6.Cg-Apoetm1Unc Tg(GFAP-APOE_i4)#Hol
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• mice require more time to habituate to a novel environment compared to wild-type mice
• at 14 to 17 months of age, mice did not perform as well as Apoetm1Unc homozygotes and Tg(GFAP-APOE_i3)37Hol Apoetm1Unc/Apoetm1Unc mice in a rotating holeboard test
• however, mice perform as well as wild-type mice in a rotating holeboard test
• mice exhibit an impairment in working memory in a radial arm maze test compared to wild-type mice
• compared to wild-type mice
• mice spend less time than wild-type mice and Apoetm1Unc homozygotes in the center of an open field
• mice exhibit increased numbers of fine movement (not related to ambulation) compared to wild-type mice


Mouse Genome Informatics
cx39
    Apoetm1Unc/Apoetm1Unc
Tg(GFAP-APOE_i4)22Hol/0

B6.Cg-Apoetm1Unc Tg(GFAP-APOE_i4)22Hol
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• in vitro, neuron outgrowth is slower than in Tg(GFAP-APOE_i3)37Hol Apoetm1Unc/Apoetm1Unc neurons
• in vitro, neurite length is shorter than in Tg(GFAP-APOE_i3)37Hol Apoetm1Unc/Apoetm1Unc neurons

cellular
• in vitro, neuron outgrowth is slower than in Tg(GFAP-APOE_i3)37Hol Apoetm1Unc/Apoetm1Unc neurons
• in vitro, neurite length is shorter than in Tg(GFAP-APOE_i3)37Hol Apoetm1Unc/Apoetm1Unc neurons


Mouse Genome Informatics
cx40
    Apoetm1Unc/Apoetm1Unc
Arhgef26tm1.1Kbur/Arhgef26tm1.1Kbur

B6.Cg-Arhgef26tm1.1Kbur Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• in the aortic arch descending thoracic aorta of mice fed a western diet compared with Apoetm1Unc homozygotes
• however, mice fed standard chow do not exhibit a significant difference


Mouse Genome Informatics
cx41
    Apoetm1Unc/Apoetm1Unc
Crptm1Hjf/Crptm1Hjf

B6.Cg-Crptm1Hjf Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• in female mice fed a low-fat, semi-synthetic diet at 16 weeks of age
• in female mice fed a low-fat, semi-synthetic diet at 16 weeks of age
• in female mice fed a low-fat, semi-synthetic diet at 12 weeks of age

cardiovascular system
• at 12 weeks of age, female mice fed a low-fat, semi-synthetic diet exhibit an increase in susceptibility to atherosclerosis in the aortic root compared with Apoetm1Unc homozygotes
• at 16 weeks of age, male mice fed a low-fat, semi-synthetic diet exhibit an increase in susceptibility to atherosclerosis in the aortic root compared with Apoetm1Unc homozygotes


Mouse Genome Informatics
cx42
    Apoetm1Unc/Apoetm1Unc
Fabp4tm1Brsp/Fabp4tm1Brsp
Fabp5tm1Hota/Fabp5tm1Hota

B6.Cg-Fabp4tm1Brsp Fabp5tm1Hota Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mice fed a high fat diet exhibit a 100% survival rate at 1 year compared to a 33% survival for Apoetm1Unc homozygotes (J:102223)

homeostasis/metabolism
• fasting serum glucose levels are reduced 48% in female mice compared to Apoetm1Unc homozygotes
• however, serum glucose levels in male mice is the same as in controls
• fasting serum cholesterol levels are 18% lower in male mice and 29% lower in female mice compared to in Apoetm1Unc homozygotes
• however, serum cholesterol levels in female mice are the same as in controls
• fasting serum triglyceride levels are 32% lower in male mice and 42% lower in female mice compared to in Apoetm1Unc homozygotes
• however, serum triglyceride levels in female mice are the same as in controls
• compared to Apoetm1Unc homozygotes
• compared to Apoetm1Unc homozygotes

cardiovascular system
• male mice exhibit a 53% reduction in mean atherosclerotic lesion and a 45% reduction in mean lesion are of the en face aorta compared to Apoetm1Unc homozygotes
• female mice exhibit a 37% reduction in mean atherosclerotic lesion and a 37% reduction in mean lesion are of the en face aorta compared to Apoetm1Unc homozygotes
• when fed a high fat diet, male mice exhibit a 26% reduction in atherosclerosis of the proximal aorta with a 78% reduction in the en face aorta lesion compared to in Apoetm1Unc homozygotes

growth/size
• body weight of male mice is 10% lower than in Apoetm1Unc homozygotes
• however, female mice weigh the same as controls


Mouse Genome Informatics
cx43
    Apoetm1Unc/Apoetm1Unc
Faslgld/Faslgld

B6.Cg-Faslgld Apoetm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• mutants on a Western diet for 12 weeks exhibit atherosclerotic lesions in the aorta (J:91058)
• aortae show higher levels of macrophage and T cell extravasation within lesions and higher levels of apoptotic cells within lesions than in single Apoe homozygotes (J:91058)
• treatment with mycophenolate mofetil decreases the severity of atherosclerosis seen in mice fed a Western diet (J:200141)
• lesion area of mutants fed a Western diet is greater than in single Apoe homozygotes, with a 3-fold increase in plaque area
• mutants on a normal diet exhibit larger atherosclerotic lesion area than single Apoe homozygotes
• aortae show macrophage and T cell extravasation within atherosclerotic lesions, showing a greater increase in macrophages and T cells than in single Apoe homozygotes

cellular
• mutants exhibit a 40% higher frequency of apoptotic material in the lymph nodes than single Fasl homozygotes
• higher levels of apoptotic cells are seen within atherosclerotic lesions than in single Apoe homozygotes

hematopoietic system
• total number of all T cell subsets is increased in the lymph nodes, however no differences in the percentages of CD4+, CD8+ or double negative T cells are seen
• on a Western and normal diet
• spleen weight is increased to almost double that seen in single Fasl homozygotes on a Western diet and 5-fold that seen in wild-type or single Apoe homozygotes (J:91058)
• treatment with mycophenolate mofetil, an immunosuppressive agent, reduces spleen weight (J:200141)
• IgG levels are elevated on both the normal and Western diet
• clearance of apoptotic material by macrophages is reduced even further compared to single Fasl homozygotes when fed a Western diet

homeostasis/metabolism
• decrease in high density lipoprotein levels compared to wild-type mice
• mutants become hypercholesterolemic on a Western diet but to a lesser extent than single Apoe homozygotes (J:91058)
• increase in low density lipoprotein (LDL) levels compared to wild-type mice
• increase in very low density lipoprotein (VLDL) levels compared to wild-type mice, however levels are lower than in single Apoe homozygotes
• mild increase in plasma triglyceride levels when fed a Western or normal diet

immune system
• aortae show macrophage and T cell extravasation within atherosclerotic lesions, showing a greater increase in macrophages and T cells than in single Apoe homozygotes
• total number of all T cell subsets is increased in the lymph nodes, however no differences in the percentages of CD4+, CD8+ or double negative T cells are seen
• on a Western and normal diet
• spleen weight is increased to almost double that seen in single Fasl homozygotes on a Western diet and 5-fold that seen in wild-type or single Apoe homozygotes (J:91058)
• treatment with mycophenolate mofetil, an immunosuppressive agent, reduces spleen weight (J:200141)
• IgG levels are elevated on both the normal and Western diet
• clearance of apoptotic material by macrophages is reduced even further compared to single Fasl homozygotes when fed a Western diet
• mutants exhibit a 40% higher frequency of apoptotic material in the lymph nodes than single Fasl homozygotes
• increase in lymph node size and weight both on the Western and normal diets; this increase is larger than in single Fasl homozygotes (J:91058)
• serum levels of anti-cardiolipin antibody are about 4-fold higher than in single Fasl homozygotes on both the normal and Western diets
• anti-nuclear antibody (ANA) titers are elevated compared to single Fasl homozygotes on a normal diet and further elevated by Western diet (J:91058)
• treatment with mycophenolate mofetil decreases the anti-nuclear antibody titer (J:200141)
• infiltration of inflammatory cells and modest crest formation

renal/urinary system
• infiltration of inflammatory cells and modest crest formation
• kidneys have larger, more cellular glomeruli (J:91058)
• treatment with mycophenolate mofetil decreases glomerular tuft size and cell count (J:200141)


Mouse Genome Informatics
cx44
    Apoetm1Unc/Apoetm1Unc
Tg(GFAP-APOE_i3)37Hol/0

B6.Cg-Tg(GFAP-APOE_i3)37Hol Apoetm1Unc/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• in vitro, neuron outgrowth is faster than in Apoetm1Unc/Apoetm1Unc Tg(GFAP-APOE_i4)22Hol neurons
• in vitro, neurite length is longer than in Apoetm1Unc/Apoetm1Unc Tg(GFAP-APOE_i4)22Hol neurons
• however, neurite outgrowth rate is equivalent to in Apoetm1Unc/Apoetm1Unc Tg(GFAP-APOE_i4)22Hol neurons when neurons are treated with RAP or anti-LRP IgG
• the ratio of lipid to Apoe in HDL particles secreted from astrocytes is lower than in wild-type astrocytes but higher than in Apoetm1Unc homozygotes

cellular
• in vitro, neuron outgrowth is faster than in Apoetm1Unc/Apoetm1Unc Tg(GFAP-APOE_i4)22Hol neurons
• in vitro, neurite length is longer than in Apoetm1Unc/Apoetm1Unc Tg(GFAP-APOE_i4)22Hol neurons
• however, neurite outgrowth rate is equivalent to in Apoetm1Unc/Apoetm1Unc Tg(GFAP-APOE_i4)22Hol neurons when neurons are treated with RAP or anti-LRP IgG


Mouse Genome Informatics
cx45
    Apoetm1Unc/Apoetm1Unc
Tg(GFAP-APOE_i4)1Hol/0

B6.Cg-Tg(GFAP-APOE_i4)1Hol Apoetm1Unc/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• the ratio of lipid to Apoe in HDL particles secreted from astrocytes is lower than in wild-type astrocytes but higher than in Apoetm1Unc homozygotes


Mouse Genome Informatics
cx46
    Apoetm1Unc/Apoetm1Unc
Msr1tm1Csk/Msr1tm1Csk

either: (involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6J * ICR) or (involves: 129P2/OlaHsd * 129X1/SvJ * 129/Sv * ICR)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• atherosclerotic plaques, but smaller than those seen in Apoetm1Unc mutant mice

homeostasis/metabolism
• increased plasma cholesterol concentrations
• plasma cholesterol concentrations greater than Apoetm1Unc mutant mice


Mouse Genome Informatics
cx47
    Apoetm1Unc/Apoetm1Unc
Hptm1Alev/Hptm1Alev

involves: 129
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• iron deposition in atherosclerotic lesions is almost two times greater than what is observed in mice that are homozygotes for just the Apoetm1Unc allele
• there is also increased amounts of oxidized lipids and proteins occurring in the plaques

immune system
• 50% more macrophages are found in atherosclerotic lesions than in mice that are homozygous for just the Apoetm1Unc allele

cellular
• 50% more macrophages are found in atherosclerotic lesions than in mice that are homozygous for just the Apoetm1Unc allele

hematopoietic system
• 50% more macrophages are found in atherosclerotic lesions than in mice that are homozygous for just the Apoetm1Unc allele


Mouse Genome Informatics
cx48
    Apoetm1Unc/Apoetm1Unc
Egr1tm1Jmi/Egr1tm1Jmi

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• 2.5 fold decrease in lesions at 14 weeks of age compared to Apoetm1Unc/tmiUnc
• 7 fold difference in lesion numbers at 24 weeks of age


Mouse Genome Informatics
cx49
    Apoetm1Unc/Apoetm1Unc
Cav1tm1Mls/Cav1tm1Mls

involves: 129/Sv * 129P2/OlaHsd * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• 70% reduction in atherosclerotic lesion area, indicating protection against the development of aortic atheromas

homeostasis/metabolism
• 1.3 to 1.5-fold increase in non-HDL plasma cholesterol levels when fed a normal or high-fat diet
• on a normal or high-fat diet
• on a normal or high-fat diet
• approximate 2.3-fold increase in plasma triglyceride when fed a normal or high-fat diet


Mouse Genome Informatics
cx50
    Apoetm1Unc/Apoetm1Unc
Lgals3tm1Poi/Lgals3tm1Poi

involves: 129/Sv * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• at 25 to 31 weeks of age, mice exhibit a lower number inflammatory infiltrate and mast cells in adventitia than Apoetm1Unc homozygotes
• at 36 to 44 months of age, mice exhibit fewer atherosclerotic lesions and atheromatous plaques compared to in Apoetm1Unc homozygotes and do not exhibit an age-related increase in lesion number, athlerosclerotic microaneurysms or periaortic vascular channels that are evident in Apoetm1Unc homozygotes

homeostasis/metabolism
• compared to in Lgals3tm1Poi homozygotes


Mouse Genome Informatics
cx51
    Apoetm1Unc/Apoetm1Unc
Tg(APPV717F)109Ili/Tg(APPV717F)109Ili

involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• by 12 months of age, mice have amyloid beta (Abeta) deposits in the hippocampus and cortex
• deposits are diffuse in appearance; deposition is prominent in dentate hilus, but little or none in molecular layer of dentate gyrus
• at 12 months, mice have high levels of insoluble Abeta42
• at 3 months, cerebral spinal fluid levels of Abeta40 and Abeta42 are elevated; Abeta40 increase is greater than in transgenic, Apoe-single null animals

homeostasis/metabolism
• by 12 months of age, mice have amyloid beta (Abeta) deposits in the hippocampus and cortex
• deposits are diffuse in appearance; deposition is prominent in dentate hilus, but little or none in molecular layer of dentate gyrus
• at 12 months, mice have high levels of insoluble Abeta42
• at 3 months, cerebral spinal fluid levels of Abeta40 and Abeta42 are elevated; Abeta40 increase is greater than in transgenic, Apoe-single null animals

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:107702


Mouse Genome Informatics
cx52
    Apoetm1Unc/Apoetm1Unc
Lpltm1Sem/Lpltm1Sem

involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• following carotid injury with ferric chloride, neointimal area is greater than in similarly treated Apoetm1Unc homozygotes
• however, the medial area of the healing blood vessel is normal
• following carotid injury with ferric chloride, the intima to media ratio is increased compared to in similarly treated Apoetm1Unc homozygotes
• following carotid injury with ferric chloride, neointimal hyperplasia induces more pronounced luminal stenosis than in similarly treated Apoetm1Unc homozygotes
• following carotid injury with ferric chloride, mice develop severe occlusive thrombi with complete degradation of the medial elastic fibers unlike in similarly treated Apoetm1Unc homozygotes
• unlike Apoetm1Unc homozygotes, mice fail to exhibit an increase in plasma triglyceride and cholesterol levels following carotid artery injury with ferric chloride and high cholesterol diet
• unlike Apoetm1Unc homozygotes, mice fail to exhibit an increase in plasma cholesterol levels following carotid artery injury with ferric chloride and high cholesterol diet
• pre-injury and at 12 weeks following aortic injury with ferric chloride, mice exhibit increased plasma cholesterol and non-HDL cholesterol levels compared with Apoetm1Unc homozygotes
• pre-injury and at 12 weeks following aortic injury with ferric chloride, mice exhibit increased plasma triglyceride levels compared with Apoetm1Unc homozygotes
• at 12 weeks following aortic injury with ferric chloride, mice exhibit severe combined hyperlipidemia compared with Apoetm1Unc homozygotes
• following carotid injury with ferric chloride, mice develop severe occlusive thrombi with complete degradation of the medial elastic fibers unlike in similarly treated Apoetm1Unc homozygotes

cardiovascular system
• following carotid injury with ferric chloride, neointimal area is greater than in similarly treated Apoetm1Unc homozygotes
• however, the medial area of the healing blood vessel is normal
• following carotid injury with ferric chloride, the intima to media ratio is increased compared to in similarly treated Apoetm1Unc homozygotes
• following carotid injury with ferric chloride, neointimal hyperplasia induces more pronounced luminal stenosis than in similarly treated Apoetm1Unc homozygotes
• following carotid injury with ferric chloride, mice develop severe occlusive thrombi with complete degradation of the medial elastic fibers unlike in similarly treated Apoetm1Unc homozygotes

Mouse Models of Human Disease
OMIM IDRef(s)
Hyperlipidemia, Familial Combined; FCHL 144250 J:151434


Mouse Genome Informatics
cx53
    Apoetm1Unc/Apoetm1Unc
Rag2tm1Fwa/Rag2tm1Fwa

involves: 129P2/OlaHsd * 129S/SvEv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• body weight of mice treated with estradiol is reduced relative to that of untreated controls

reproductive system
• in response to estradiol treatment (J:59156)

homeostasis/metabolism
• reduced total cholesterol in response to estradiol treatment
• in response to estradiol treatment

cardiovascular system
• increased fatty streak lesions in the aortic root in response to estradiol treatment


Mouse Genome Informatics
cx54
    Apoetm1Unc/Apoetm1Unc
Rag2tm1Fwa/Rag2+

involves: 129P2/OlaHsd * 129S/SvEv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• body weight of mice treated with estradiol is reduced relative to that of untreated controls

reproductive system
• in response to estradiol treatment (J:59156)

homeostasis/metabolism
• reduced total cholesterol in response to estradiol treatment
• in response to estradiol treatment

cardiovascular system
• decreased fatty streak lesions in the aortic root in response to estradiol treatment


Mouse Genome Informatics
cx55
    Apoetm1Unc/Apoetm1Unc
Il1rntm1Dih/Il1rntm1Dih

involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• increased death rate on a high cholesterol diet

homeostasis/metabolism
• significantly reduced plasma cholesterol levels relative to Apoetm1Unc homozygous controls on a normal diet

growth/size
• relative to singly homozyous Apoetm1Unc

immune system
• massive infiltration of macrophage in the aortic arch

cardiovascular system
N
• no intimal thickening occurs on a high cholesterol diet (J:132570)
• elastic lamina in the media of the coronary arteries is destroyed
• elastic lamina in the media of the aortic root is destroyed

cellular
• massive infiltration of macrophage in the aortic arch

hematopoietic system
• massive infiltration of macrophage in the aortic arch


Mouse Genome Informatics
cx56
    Apoetm1Unc/Apoetm1Unc
Cd36tm1Mfe/Cd36tm1Mfe

involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• females with reduced triacyl glycerol on a high fat diet
• females with higher cholesterol levels on a normal fat diet
• more subcutaneous xanthomas than found when Apoetm1Unc is alone

cardiovascular system
• 76% reduction in atherosclerotic lesions in the aorta when on a high fat diet as compared to Apoetm1Unc
• area covered by lesions is 5% as compared to 30% in Apoetm1Unc homozygous males
• lesions 45% smaller in size in males and mostly restricted to the aortic arch rather than throughout the aortic tree
• female lesions closer in size to Apoetm1Unc controls
• smaller lesions on a low fat diet as well and also for females
• lesions composed of more densely packed lipid laden foam cells

growth/size
• gain significantly more weight on a high fat diet than Apoetm1Unc controls
• on a normal diet only males are significantly heavier than controls

immune system
• considerably less modified LDL is bound and cellular uptake is reduced
• native LDL binding is normal

cellular

hematopoietic system
• considerably less modified LDL is bound and cellular uptake is reduced
• native LDL binding is normal


Mouse Genome Informatics
cx57
    Apoetm1Unc/Apoetm1Unc
Clutm1Jakh/Clutm1Jakh
Tg(APPV717F)109Ili/Tg(APPV717F)109Ili

involves: 129P2/OlaHsd * 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• at 6 months of age, most mice have substantial amyloid beta (Abeta) deposits
• by 12 months of age, mice have more amyloid beta (Abeta) deposits in the hippocampus and cortex than other genotypes
• Abeta deposits are more numerous and fill all parts of hippocampus and some of the cortex by 12 months; abundant compact and diffuse plaques are observed
• mice have greater levels of thioflavine-S-positive (fibrillar) Abeta deposits than other genotypes, similar to transgenic homozygotes with normal Apoe and Clu
• at 3 months, cerebral spinal fluid levels of Abeta40 and Abeta42 are elevated

homeostasis/metabolism
• mice have significant amyloid burden, greater than shown by other genotypes
• at 12 months, mice have highest tissue levels of soluble Abeta40 and Abeta42, with high levels of insoluble Abeta42
• at 3 months, mice have higher levels of carbonate soluble Abeta40 and Abeta42 compared to other genotypes
• at 6 months of age, most mice have substantial amyloid beta (Abeta) deposits
• by 12 months of age, mice have more amyloid beta (Abeta) deposits in the hippocampus and cortex than other genotypes
• Abeta deposits are more numerous and fill all parts of hippocampus and some of the cortex by 12 months; abundant compact and diffuse plaques are observed
• mice have greater levels of thioflavine-S-positive (fibrillar) Abeta deposits than other genotypes, similar to transgenic homozygotes with normal Apoe and Clu
• at 3 months, cerebral spinal fluid levels of Abeta40 and Abeta42 are elevated

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:107702


Mouse Genome Informatics
cx58
    Apoetm1Unc/Apoetm1Unc
Ncf1tm1Shl/Ncf1tm1Shl

involves: 129P2/OlaHsd * 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• aneurysms reduced to 17% of animals rather than 40% as seen in Apoetm1Unc mice
• aneurisms reduced to 17% of animals rather than 90% as seen in Apoetm1Unc mice
• diameter and weight of aneurisms considerably reduced relative to Apoetm1Unc mice but still enlarged relative to controls
• development of atherosclerosis is considerably reduced 2 weeks after ligation of the left common carotid as compared to Apoetm1Unc
• atherosclerosis continues to be reduced 3 weeks after ligation of the left common carotid as compared to Apoetm1Unc but no longer significantly
• angiotensin-II induced affect on blood pressure is blunted

immune system
• leukocyte infiltration into the adventitia of the aorta is attenuated


Mouse Genome Informatics
cx59
    Apoetm1Unc/Apoetm1Unc
Scarb1tm1Kri/Scarb1tm1Kri

involves: 129P2/OlaHsd * 129S2/SvPas * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median survival time of approximately 6 weeks

cardiovascular system
• in the coronary arteries
• coronary artery occlusion
• at 31 days of age small myocardial infarctions are seen and by 43 days of age extensive myocardial infarctions are present
• develop occlusive, atherosclerotic coronary artery disease after 21 days of age
• increase in the heart to body weight ratio in mice over 21 days of age


Mouse Genome Informatics
cx60
    Apoetm1Unc/Apoetm1Unc
Fut4tm1Jbl/Fut4tm1Jbl
Fut7tm1Jbl/Fut7tm1Jbl

involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• decreased lesion size at 6 months of age


Mouse Genome Informatics
cx61
    Apoetm1Unc/Apoetm1Unc
Scarb1tm1Kri/Scarb1tm1Kri

involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• non uniform cell populations
• target-like appearance
• intracellular inclusions
• mitochondria present
• often spiculated
• reticulocytes appear in the circulation
• a systemic process interferes with reticulocyte maturation
• abnormally large but with normal cellular hemoglobin levels


Mouse Genome Informatics
cx62
    Apoetm1Unc/Apoetm1Unc
Itgb3tm1Hyn/Itgb3tm1Hyn

involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• at 16 weeks of age after 10 weeks on a western style diet only 52% of mice compared to 100% survival for diet matched Ldlr single mutants
• no increase in mortality is seen in mice kept on a standard chow diet
• similar to that in Itgb3 single mutants
• only 62% survival to weaning for compared to 96% survival in mice null for Apoe alone
• at 12 weeks of age after 6 weeks on a western style diet, survival is reduced to 38% for mice compared to 96% for diet matched Apoe single mutants

immune system
• isolated small foci of mononuclear cells are present in lung after 6 weeks of high-fat feeding
• in mice fed a high fat diet pneumonitis is the cause of death

respiratory system
• isolated small foci of mononuclear cells are present in lung after 6 weeks of high-fat feeding
• in mice fed a high fat diet pneumonitis is the cause of death

hematopoietic system
• western diet fed mice are anemic compared to diet matched mice null for Apoe alone

growth/size
• after 6 weeks on a western diet mice weighed less than diet matched Apoe single mutants

homeostasis/metabolism
• after 6 weeks on a western diet mice weighed less than diet matched Apoe single mutants

cardiovascular system
• on a western diet, lesions are 2.6 fold greater at the arch, 3.3 fold greater at the thoracic aorta, and 5.6-fold greater at the abdominal aorta compared to diet matched Apoe single mutants
• on chow diet at approximately 11 months of age, lesions are 2.4 fold greater at the arch, 3 fold greater at the thoracic aorta than in diet matched Apoe single mutants.


Mouse Genome Informatics
cx63
    Apobec1tm1Chan/Apobec1tm1Chan
Apoetm1Unc/Apoetm1Unc

involves: 129P2/OlaHsd * 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• circulating VLDL/LDL cholesterol levels are decreased compared to in Apoetm1Unc homozygotes
• circulating VLDL/LDL cholesterol levels are increased compared to in Apobec1tm1Chan homozygotes and wild-type mice
• when fed a chow, mice exhibit decreased total serum cholesterol compared with Apoetm1Unc homozygotes
• when fed a chow or a Western-type diet for 2 or 4 weeks, mice exhibit decreased total serum cholesterol compared with Apobec1tm1Chan homozygotes and wild-type mice
• when fed a chow diet or a Western-type diet for 2 or 4 weeks, serum triglyceride is higher than in wild-type mice
• when fed a Western-type diet for 2 or 4 weeks, mice exhibit increased serum triglyceride compared with Apobec1tm1Chan or Apoetm1Unc homozygotes
• when fed a Western-type diet for 10 weeks, mice exhibit increased serum triglyceride compared with Apoetm1Unc homozygotes


Mouse Genome Informatics
cx64
    Apoetm1Unc/Apoetm1Unc
Ccr1tm1Gao/Ccr1tm1Gao

involves: 129P2/OlaHsd * 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• increased plaque size on a high fat diet

immune system
• increased number of secreting cells


Mouse Genome Informatics
cx65
    Apoetm1Unc/Apoetm1Unc
Timp1tm1Pds/Y

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• males fed an atherogenic, high-fat diet for 10 or 22 weeks develop a higher number of ruptures in the aortic media, in which all elastic laminae are digested and infiltrated with macrophages and form pseudo-microaneurysms, than single homozygous Apoe mutant males (J:103082)


Mouse Genome Informatics
cx66
    Apoetm1Unc/Apoetm1Unc
Ttpatm1Far/Ttpatm1Far

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Morphology of aortic lesions in Apoetm1Unc/Apoetm1Unc and Apoetm1Unc/Apoetm1Unc Ttpatm1Far/Ttpatm1Far mice

homeostasis/metabolism
• at 30 weeks of age, chow-fed double homozygous mutant females show no significant differences in total plasma cholesterol levels, HDL cholesterol levels or plasma ascorbate and urate levels relative to single Apoetm1Unc homozygotes
• however, double mutant females display a ~2-fold increase in total F2-isoprostane levels in the proximal and distal aorta, indicating that increased lipid peroxidation contributes to lesion development

cardiovascular system
• at 30 weeks of age, chow-fed double homozygous mutant females exhibit a ~36% increase in total aortic lesion area relative to single Apoetm1Unc homozygotes
• specifically, double mutant females have 42% and 53% larger aortic lesions in the aortic arch and thorax region, respectively, relative to single Apoetm1Unc homozygotes; no differences in lesion size in the abdominal aorta are observed
• double mutant aortic root lesions exhibit more complex features, including a large necrotic core, numerous needle-shaped lucencies indicative of cholesterol crystals, and fibrous capping from smooth muscle cells


Mouse Genome Informatics
cx67
    Apoetm1Unc/Apoetm1Unc
Ttpatm1Far/Ttpa+

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• chow-fed mice heterozygous for Ttpatm1Far and homozygous for Apoetm1Unc show a 24% reduction of plasma alpha-tocopherol levels relative to single Apoetm1Unc homozygotes

cardiovascular system
• at 30 weeks of age, chow-fed female mice heterozygous for Ttpatm1Far and homozygous for Apoetm1Unc have 13% larger atherosclerotic lesions in the aortic arch region relative to single Apoetm1Unc homozygotes


Mouse Genome Informatics
cx68
    Apoetm1Unc/Apoetm1Unc
Ccr2tm1Ifc/Ccr2tm1Ifc

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• in mice fed a high fat diet for 5, 9, and 13 weeks, atherosclerotic lesions are smaller than in similarly treated Apoetm1Unc homozygotes
• however, serum cholesterol levels are the same as in Apoetm1Unc homozygotes

immune system
• fewer macrophages in mice fed a high fat diet are present in the aorta compared to in similarly treated Apoetm1Unc homozygotes

cellular
• fewer macrophages in mice fed a high fat diet are present in the aorta compared to in similarly treated Apoetm1Unc homozygotes

hematopoietic system
• fewer macrophages in mice fed a high fat diet are present in the aorta compared to in similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cx69
    Apoetm1Unc/Apoetm1Unc
Ccr2tm1Ifc/Ccr2+

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• atherosclerotic lesions in mice fed a high fat diet for 5 weeks are smaller than in similarly treated Apoetm1Unc homozygotes
• however, no difference was observed at later time points


Mouse Genome Informatics
cx70
    Apoetm1Unc/Apoetm2(APOE_i3)Yhg
Tg(PDGFB-APPSwInd)20Lms/0

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• aged mice exhibit reduced amyloid plaques compared to Apoetm2(APOE_i3)Yhg/Apoetm2(APOE_i3)Yhg Tg(PDGFB-APPSwInd)20Lms mice

homeostasis/metabolism
• aged mice exhibit reduced amyloid plaques compared to Apoetm2(APOE_i3)Yhg/Apoetm2(APOE_i3)Yhg Tg(PDGFB-APPSwInd)20Lms mice


Mouse Genome Informatics
cx71
    Apoetm1Unc/Apoetm3(APOE_i4)Yhg
Tg(PDGFB-APPSwInd)20Lms/0

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• aged mice exhibit reduced amyloid plaques compared to Apoetm3(APOE_i4)Yhg/Apoetm3(APOE_i4)Yhg Tg(PDGFB-APPSwInd)20Lms mice

homeostasis/metabolism
• aged mice exhibit reduced amyloid plaques compared to Apoetm3(APOE_i4)Yhg/Apoetm3(APOE_i4)Yhg Tg(PDGFB-APPSwInd)20Lms mice


Mouse Genome Informatics
cx72
    Apoetm1Unc/Apoetm1Unc
Soat1tm1Far/Soat1tm1Far

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Apoetm1Unc/Apoetm1Unc Soat1tm1Far/Soat1tm1Far mice display severe xanthomatosis

homeostasis/metabolism
• free cholesterol content of the skin is 6- to 7-fold higher than in single Apoe mutant controls at 4 months of age
• by 120 days of age, mean serum cholesterol levels are lower in double mutants than in single Apoe homozygotes fed a chow diet; disparity in cholesterol levels is more marked and occurs at an earlier age in mutants fed a Western diet
• reduced VLDL and IDL cholesterol compared to single Apoe homozygotes
• mutants fed a Western diet exhibit a massive cholesterol xanthoma by 3-4 months of age
• free cholesterol crystal deposits are seen in brains of mutants fed a Western diet for 3 months, mostly near the choroid plexus

cardiovascular system
• mutants fed a Western diet develop atherosclerotic lesions, however lesions are smaller than in single Apoe homozygotes
• aortic lesion composition differs from that in Apoe homozygotes, with lower neutral lipid content and fewer cholesterol crystals and a paucity of macrophages in the most advanced lesions

immune system
• cholesterol deposition in the skin is accompanied by a severe, pleomorphic inflammatory cell infiltrate with features of acute and chronic inflammation, including large numbers of neutrophils, multinucleated giant cells with occasional intracellular cholesterol clefts, and frequent mononuclear cells, lymphocytes, and plasma cells

nervous system
• free cholesterol crystal deposits are seen in brains of mutants fed a Western diet for 3 months, mostly near the choroid plexus

integument
• cholesterol deposition in the skin is accompanied by a severe, pleomorphic inflammatory cell infiltrate with features of acute and chronic inflammation, including large numbers of neutrophils, multinucleated giant cells with occasional intracellular cholesterol clefts, and frequent mononuclear cells, lymphocytes, and plasma cells
• by 2-3 months of age, fur appears dull and mutants show pruritus
• diffuse hair loss occurs by 5-6 months of age and leads to severe lesions
• free cholesterol content of the skin is 6- to 7-fold higher than in controls at 4 months of age
• mutants fed a Western diet exhibit more severe skin changes and at an earlier age (6 weeks) than wild-type or mutants fed a chow diet
• the dermis exhibits diffuse needle-shaped lucencies indicative of cholesterol crystals; crystals appear predominantly extracellularly and are seen in or below the reticular dermis
• deeper layers of the dermis show marked proliferation of fibroblasts and extensive collagen deposition
• hyperkeratosis at the skin surface
• develop severe skin lesions within months when fed a chow diet
• by 2-3 months of age, show pruritus
• by 5-6 months of age, excoriation occurs and leads to severe lesions


Mouse Genome Informatics
cx73
    Apoetm1Unc/Apoetm1Unc
Soat2tm1Far/Soat2tm1Far

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• near absence of atherosclerotic lesions after 27 weeks on a CHOW diet
• near absence of atherosclerotic lesions after 9 weeks on a Western diet

homeostasis/metabolism
• 58% increase in serum HDL cholesterol levels compared to Apoetm1Unc/Apoetm1Unc control mice
• 60% reduction in total serum cholesterol compared to Apoetm1Unc/Apoetm1Unc control mice, primarily due to a reduction in plasma cholesterol esters
• plasma free cholesterol is reduced by 18% compared to Apoetm1Unc/Apoetm1Unc control mice
• 90% increase in total serum triglycerides compared to Apoetm1Unc/Apoetm1Unc control mice
• increase in the activity of the major enzyme responsible for synthesizing cholesterol esters in the plasma, lecithin/cholesterol acyltransferase


Mouse Genome Informatics
cx74
    Angptl3tm1Lex/Angptl3tm1Lex
Apoetm1Unc/Apoetm1Unc

involves: 129P2/OlaHsd * 129S5/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• serum cholesterol levels are 49% lower than in Apoe null homozygote controls
• serum triglyceride levels are 86% lower than in Apoe null homozygote controls


Mouse Genome Informatics
cx75
    Apoetm1Unc/Apoetm1Unc
Mmp9tm1Tvu/Mmp9tm1Tvu

involves: 129P2/OlaHsd * 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• following temporary ligation, mice develop intimal atherosclerotic plaques with reduced volume, length, smooth muscle cells, and intraplaque foam cells and macrophages compared with similarly treated Apoetm1Unc homozygotes
• following temporary ligation, fewer smooth muscle cells are found in atherosclerotic plaques compared to in similarly treated Apoetm1Unc homozygotes

immune system
• following temporary ligation, fewer foam cells and macrophages are found in atherosclerotic plaques compared to in similarly treated Apoetm1Unc homozygotes

muscle
• following temporary ligation, fewer smooth muscle cells are found in atherosclerotic plaques compared to in similarly treated Apoetm1Unc homozygotes

hematopoietic system
• following temporary ligation, fewer foam cells and macrophages are found in atherosclerotic plaques compared to in similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cx76
    Apoetm1Unc/Apoetm1Unc
Spp1tm1Blh/Spp1tm1Blh

involves: 129P2/OlaHsd * 129S6/SvEvTac * Black Swiss * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• Angiotensin II-treated mice exhibit reduced abdominal aortic aneurysm incidence and diameter compared with similarly treated Apoetm1Unc homozygotes
• Angiotensin II-induced atherosclerotic lesions exhibit reduced medial inflammation, lesion area, cellularity, macrophage viability, and foam cells compared to in similarly treated Apoetm1Unc homozygotes
• however, untreated aged male mice exhibit normal atherosclerotic lesion development

immune system
• macrophage viability in Angiotensin II-treated mice is lower than in similarly treated Apoetm1Unc homozygotes

hematopoietic system
• macrophage viability in Angiotensin II-treated mice is lower than in similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cx77
    Apoetm1Unc/Apoetm1Unc
Spp1tm1Blh/Spp1+

involves: 129P2/OlaHsd * 129S6/SvEvTac * Black Swiss * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• Angiotensin II-induced atherosclerotic lesions exhibit reduced lesion area compared to in similarly treated Apoetm1Unc homozygotes


Mouse Genome Informatics
cx78
    Apoetm1Unc/Apoetm1Unc
Cyp19a1tm1Esi/Cyp19a1tm1Esi

involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• increased body weight at 3, 6, and 12 months of age

cardiovascular system
• 3 month old mutants exhibit small aortic root lesions that are extensive at 6 months of age
• double mutants tend to have slightly larger lesion sizes than single Apoe mutants
• mutants develop large atherosclerotic lesions in the aortic root by 12 months of age; lesions are advanced in development and show a clear fibrous component
• however there is little evidence of atherosclerotic plaque formation within the thoracic aorta with only small lesion development seen in the thoracic aorta at 12 months of age
• mutants have moderately increased mean arterial blood pressure at 3 months of age
• mutants develop hypertension by 6 months of age which is sustained in older animals

adipose tissue
• mutants exhibit an increase in adipocyte size with a larger mean diameter compared to wild-type adipocytes, however no difference in the number of individual adipocytes
• increase in gonadal adipose

homeostasis/metabolism
• 3 month old mutants show a small elevation in baseline blood glucose concentration after an overnight fast
• mutants of all ages show reduced plasma insulin levels
• random-fed non-fasting mutants show an increase in serum cholesterol levels
• plasma levels of C-reactive protrein (CRP), IL-6, and TNF-alpha are increased in 12 month old mutants
• mutants administered a bolus of glucose show elevated plasma glucose
• 3 month old mutants show a blunted plasma glucose response in response to exogenous insulin administration; this blunted response becomes more pronounced with age

immune system
• plasma levels of C-reactive protrein (CRP), IL-6, and TNF-alpha are increased in 12 month old mutants

liver/biliary system
• from 6 months of age, livers begin to show yellow coloration
• increase in liver weight at 3 and 6 months of age
• 3 month old mutants start to show small lipid droplets forming within livers which become more pronounced at 6 and 12 months of age


Mouse Genome Informatics
cx79
    Apoetm1Unc/Apoetm1Unc
Lipgtm1Tq/Lipgtm1Tq

involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• when fed a high fat diet, male mice exhibit a 2-fold increase in serum cholesterol compared to in either single homozygote on either a normal or high fat diet
• compared to in Apoetm1Unc homozygotes
• compared to in wild-type mice
• compared to in wild-type mice
• in male mice on a high fat diet

cardiovascular system
• atherosclerotic lesions contain fewer macrophage infiltration than in Apoetm1Unc homozygotes
• monocyte/macrophage binding to atherosclerotic lesions in vitro is reduced compared to in Apoetm1Unc homozygotes
• formation of atherosclerotic plaques is attenuated compared to in Apoetm1Unc homozygotes
• when fed a normal diet, atherosclerotic lesions are 67% smaller in females and 71% smaller in males compared to in Apoetm1Unc homozygotes
• when fed a high fat diet, atherosclerotic lesion formation is attenuated in male mice and lesion size is decreased 24% compared to in Apoetm1Unc homozygotes


Mouse Genome Informatics
cx80
    Apoetm1Unc/Apoetm1Unc
Dp(17Nfkbil1-Olfr91)1Cogr/0

involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Decreased susceptibility to atherosclerosis in Apoetm1Unc/Apoetm1Unc Dp(17Nfkbil1-Olfr91)1Cogr/0 mice

cardiovascular system
• mice fed a high fat diet develop smaller plaques than in Apoe homozygotes

homeostasis/metabolism
N
• mice fed a high fat diet exhibit the same cholesterol and glucose serum levels and glucose tolerance as Apoetm1Unc homozygotes (J:190754)


Mouse Genome Informatics
cx81
    Apoetm1Unc/Apoetm1Unc
Ldlrtm1Her/Ldlrtm1Her

involves: 129P2/OlaHsd * 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• plasma cholesterol on a high fat diet reaches 4120 mg/dl
• triglyceride levels are unaffected by diet


Mouse Genome Informatics
cx82
    Soat1tm1Ishi/Soat1tm1Ishi
Apoetm1Unc/Apoetm1Unc

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Cutaneous xanthomatosis and alopecia in Soat1tm1Ishi/Soat1tm1Ishi Apoetm1Unc/Apoetm1Unc and Soat1tm1Ishi/Soat1tm1Ishi Ldlrtm1Her/Ldlrtm1Her mice

vision/eye

homeostasis/metabolism
• adrenocortical lipid depletion
• increased serum cholesterol levels
• hypercholesterolemia when fed a high fat diet
• cutaneous xanthomatosis

integument
• macrophage infiltration of dermis
• rough skin

endocrine/exocrine glands


Mouse Genome Informatics
cx83
    Apobec1tm1Ishi/Apobec1tm1Ishi
Apoetm1Unc/Apoetm1Unc

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• plasma levels of triglycerides are greater (238.0+/-113.3%) than in the Apoetm1Unc homozygote (98.1+/-91.1%)
• plasma cholesterol levels are lower (436.5+/-59.2mg/dl) than in Apoetm1Unc homozygotes (621.5+/-126.7mg/dl)


Mouse Genome Informatics
cx84
    Apoetm1Unc/Apoetm1Unc
Spp1tm1Rit/Spp1tm1Rit

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• atherosclerotic lesions in female mice are 34% smaller than in Apoetm1Unc homozygotes
• male mice exhibit increased vascular calcification of aortic root sections compared to in Apoetm1Unc homozygotes

homeostasis/metabolism
• total circulating cholesterol and non-HDL-cholesterol levels are increased 1.5-fold in male mice compared to in Apoetm1Unc homozygotes
• plasma triglyceride levels are increased 4-fold in male mice compared to in Apoetm1Unc homozygotes


Mouse Genome Informatics
cx85
    Apoetm1Unc/Apoetm1Unc
Spp1tm1Rit/Spp1+

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• atherosclerotic lesions in female mice are 43% smaller than in Apoetm1Unc homozygotes with reduced aortic wall inflammation

homeostasis/metabolism