Analysis Tools
mortality/aging
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• 35% dead by 18 months
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cardiovascular system
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• in perhexiline-treated mice fed a high-fat diet
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• 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)
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• arterioles of the vascular pole show a "foamy" degeneration of smooth muscle cells
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• 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
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• 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
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atherosclerotic lesions
(
J:60364
, J:73202
, J:91058
, J:97385
, J:101576
, J:105736
, J:108154
, J:142083
)
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• 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)
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• 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)
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• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
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• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
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• vascular stenosis is significantly increased in homozygotes fed an atherosclerotic diet vs a normal diet
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• lumen stenosis of the spiral modiolar artery in the cochlea is exacerbated by an atherosclerotic diet relative to a normal diet
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• at 13 months, homozygotes show a 23% increase in heart weight relative to wild-type mice (186 7.1 vs. 151 2.5 mg)
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• at 13 months, homozygotes show a 59% increase in heart weight-to-body weight ratio relative to wild-type mice
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• 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
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• under anesthesia, homozygotes exhibit elevated flow velocities suggesting elevated cardiac output
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• under anesthesia, homozygotes appear to exhibit significantly increased stroke volume
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• under anesthesia, homozygotes appear to exhibit significantly reduced peripheral vascular resistance and compliance in the presence of normal blood pressures
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• pulse wave velocity is insignificantly elevated at 4 months
• pulse wave velocity significantly elevated at 13 months
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• 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
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• immunostaining of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase), ACTA2 (a smooth muscle marker) and EdU showed significantly increased expression of ATIC in proliferative vascular smooth muscle cells (VSMCs) of atherosclerotic plaques in mice fed a Western diet for 3 months
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• in response to precontraction with phenylephrine and relaxation with acetylcholine, mice supplemented with adenosine dialdehyde (ADA; an inhibitor of S-adenosylhomocysteine hydrolase) or treated with a short hairpin RNA targeting Ahcy with or without indomethacin exhibit endothelial dysfunction compared with control mice
• however, relaxation in response to nitroprusside is normal
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• 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
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• aortae show macrophage and T cell extravasation within atherosclerotic lesions
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muscle
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• immunostaining of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase), ACTA2 (a smooth muscle marker) and EdU showed significantly increased expression of ATIC in proliferative vascular smooth muscle cells (VSMCs) of atherosclerotic plaques in mice fed a Western diet for 3 months
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• in response to precontraction with phenylephrine and relaxation with acetylcholine, mice supplemented with adenosine dialdehyde (ADA; an inhibitor of S-adenosylhomocysteine hydrolase) or treated with a short hairpin RNA targeting Ahcy with or without indomethacin exhibit endothelial dysfunction compared with control mice
• however, relaxation in response to nitroprusside is normal
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• 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
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• relaxation response to acetylcholine in blood vessels is significantly attenuated at 13 months of age
• maximal response to acetylcholine is considerably reduced
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homeostasis/metabolism
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• in perhexiline-treated mice fed a high-fat diet
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• decrease in plasma total homocysteine levels
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• decreased HDL/total cholesterol ratio
• decreased HDL/LDL ratio
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increased circulating cholesterol level
(
J:73202
, J:91058
, J:97385
, J:101576
, J:104609
, J:125978
, J:133606
)
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• 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)
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• in perhexiline-treated mice fed a high-fat diet
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• 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)
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• 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)
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• 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)
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• 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
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• 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
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• reduced aortic concentration in response to precontraction with phenylephrine and relaxation with acetylcholine in mice supplemented with ADA or treated with a short hairpin RNA targeting Ahcy
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• 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)
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• activity of cholesterol synthesis enzyme HMG-CoA reductase is reduced up to 60% in aging mice compared to 30% in wild-type aging mice
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• mice fed a Western diet for 3 months show significantly upregulated expression of ATIC -- a bifunctional enzyme of the last 2 steps in de novo purine synthesis (DNPS) -- in proliferative VSMCs of atherosclerotic plaques
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growth/size/body
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• at 13 months, homozygotes show a 23% increase in heart weight relative to wild-type mice (186 7.1 vs. 151 2.5 mg)
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• at 13 months, homozygotes show a 59% increase in heart weight-to-body weight ratio relative to wild-type mice
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• 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)
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• nose to rump length less than controls at both 1 and 3 months
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• body weight was less than controls at 3 months but identical at 8 months
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• increased spleen weight while the thymus weight remains normal
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hematopoietic system
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• increased spleen weight while the thymus weight remains normal
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• 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)
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• decreased relative to controls
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• with induction of SLE by cGVH, levels are slightly decreased compared to wild-type
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• newly formed B cells are significantly increased compared to wild-type
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• increased 2-fold compared to wild-type
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• increased numbers of cytokine producing T cells
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• 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)
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• spleen cells display polyclonal B cell activation, with increased expression of MHC II, Fas, and CD86 and lower expression of CD21, CD22, and CD23
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• mutants with cGVH-induced SLE show greatly increased levels compared to wild-type controls or untreated mutants
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• IgM response to tetanus toxoid is significantly increased as compared to controls
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cellular
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• in perhexiline-treated mice fed a high-fat diet
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• increased rate of bone formation
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• regular exercise fails to reduce endogenous oxidant load and mitochondrial damage in hypercholesterolemic mutant mice
(J:97385)
• in contrast, regular exercise results in reduced mitochondrial damage and oxidant load and increased SOD2 and adenine nucleotide translocator activities in normocholesterolemic control mice
(J:97385)
• in mice supplemented with ADA or treated with a short hairpin RNA targeting Ahcy
(J:298071)
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hearing/vestibular/ear
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• endothelial nitric oxide synthase (eNOS) in mutant cochlea is distinctly reduced
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• on an atherosclerotic diet, homozygotes display a sclerosed and atrophic basilar membrane
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• 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
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• 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
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• 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
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• on an atherosclerotic diet, homozygotes display a sclerosed and atrophic stria vascularis
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• on an atherosclerotic diet, homozygotes display a sclerosed and atrophic tectorial membrane
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• 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
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• 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
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nervous system
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• 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
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• 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
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• 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
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• 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
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immune system
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• increased spleen weight while the thymus weight remains normal
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• decreased relative to controls
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• with induction of SLE by cGVH, levels are slightly decreased compared to wild-type
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• newly formed B cells are significantly increased compared to wild-type
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• increased 2-fold compared to wild-type
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• increased numbers of cytokine producing T cells
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• 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)
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• aortae show macrophage and T cell extravasation within atherosclerotic lesions
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• spleen cells display polyclonal B cell activation, with increased expression of MHC II, Fas, and CD86 and lower expression of CD21, CD22, and CD23
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• decreased antigen specific delayed hypersensitivity response
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• mutants with cGVH-induced SLE show greatly increased levels compared to wild-type controls or untreated mutants
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• IgM response to tetanus toxoid is significantly increased as compared to controls
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• production is reduced when fed a high cholesterol diet
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• 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
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• after induction of cGVH-SLE, mice display greatly increased levels of anti-chromatin antibodies compared to wild-type controls or non-cGVH mutants
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• after induction of cGVH-SLE, mice display greatly increased levels compared to wild-type controls or non-cGVH-SLE mutants
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behavior/neurological
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• 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
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• elevated thigmotaxis in Morris maze tests
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renal/urinary system
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• arterioles of the vascular pole show a "foamy" degeneration of smooth muscle cells
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• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
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• increased glomerular tuft area
• glomerular cell numbers are increased
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• at times mesangiolysis is associated with ballooning dilatation ("microaneurysm") of adjacent glomerular capillaries
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• progressive increase in glomerular matrix, already evident at 24 weeks, associated with accumulation of laminin and collagen IV
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• loss of mesangial matrix sometimes at 36 weeks but never at 24 weeks or in controls
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• 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
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liver/biliary system
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• 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
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vision/eye
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• perinuclear vacuolation on a high cholesterol diet
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• cell numbers reduced
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• cell numbers reduced
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• 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)
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taste/olfaction
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• 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
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skeleton
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• higher bone mineral density in vertebral bodies
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• increased bone volume to tissue volume ratio in the vertebra at both 3 and 8 months and in the tibia at 8 months of age
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• increased trabecular bone volume in the vertebra at both 3 and 8 months and in the tibia at 8 months of age
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• in vertebral bodies and tibia
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• increased number of trabeculae in vertebral bodies
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• increased rate of bone formation
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respiratory system
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• fewer but larger alveoli at 3 months of age
• less surface area to volume
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• percent increase in hysteresivity with age greater than in controls
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• lung volume similar to controls at 3 months but 2.5 fold greater at 8 months of age
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• resistance to airflow greater than controls at 3 months but not at 8 months of age
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• dynamic and static compliance greater than controls at 8 months of age
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integument
skin lesions
(
J:73202
)
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• progressive skin lesions, mainly seen as eruptive xanthomas on shoulder and back areas with lipids and extracellular matix as the predominant components
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