Cardiovascular mortality is 10 to 20 times increased in patients with
chronic renal failure (CRF). Risk factors for
atherosclerosis are abundant in patients with CRF. However, the pathogenesis of
cardiovascular disease in CRF remains to be elucidated. The effect of CRF on the development of
atherosclerosis in
apolipoprotein E-deficient male mice was examined. Seven-week-old mice underwent 5/6
nephrectomy (CRF, n = 28), unilateral
nephrectomy (UNX, n = 24), or no surgery (n = 23). Twenty-two weeks later, CRF mice showed increased aortic plaque area fraction (0.266 +/- 0.033 versus 0.045 +/- 0.006; P < 0.001), aortic
cholesterol content (535 +/- 62 versus 100 +/- 9 nmol/cm(2) intimal surface area; P < 0.001), and aortic root plaque area (205,296 +/- 22,098 versus 143,662 +/- 13,302 micro m(2); P < 0.05) as compared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic mice contained CD11b-positive macrophages and showed strong staining for
nitrotyrosine. Systolic BP and plasma
homocysteine concentrations were similar in uremic and nonuremic mice. Plasma
urea and
cholesterol concentrations were elevated 2.6-fold (P < 0.001) and 1.5-fold (P < 0.001) in CRF compared with no-surgery mice. Both variables correlated with aortic plaque area fraction (r(2) = 0.5, P < 0.001 and r(2) = 0.3, P < 0.001, respectively) and with each other (r(2) = 0.5, P < 0.001). On multiple linear regression analysis, only plasma
urea was a significant predictor of aortic plaque area fraction. In conclusion, the present findings suggest that
uremia markedly accelerates
atherogenesis in
apolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasma
homocysteine levels, or total plasma
cholesterol concentrations. Thus, the CRF
apolipoprotein E-deficient mouse is a new model for studying the pathogenesis of accelerated
atherosclerosis in
uremia.