Inhibition of the renin-angiotensin system abolishes the proatherogenic effect of uremia in apolipoprotein E-deficient mice

Objective - Uremia accelerates atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. We examined whether this effect may be preventable by pharmacological blockade of the renin-angiotensin system (RAS). Methods and Results - Uremia was induced in apoE(-/-) mice by 5/6 nephrectomy (NX). Treatment with the angiotensin converting enzyme inhibitor enalapril (2 or 12 mg/kg/d) from week 4 to 36 after NX reduced the aortic plaque area fraction from 0.23 +/- 0.02 (n = 20) in untreated mice to 0.11 +/- 0.01 (n = 21) and 0.08 +/- 0.01 (n = 23), respectively (P < 0.0001); the aortic plaque area fraction was 0.09 +/- 0.01 (n = 22) in sham-operated controls. Enalapril from week 20 to 44 after NX also retarded the progression of atherosclerosis. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) and concentrations of IgM antibodies against oxidized low density lipoprotein (OxLDL) increased after NX (P < 0.01). Enalapril (12 mg/kg/d) attenuated these increases (P < 0.05) and reduced aortic expression of vascular cell adhesion molecule (VCAM)-1 mRNA (P < 0.05). Atherosclerosis in NX mice was also reduced by losartan (an angiotensin II receptor-blocker), but not when blood pressure was lowered with hydralazine (a non-RAS-dependent vasodilator). Conclusion - The results suggest that inhibition of RAS abolishes the proatherogenic effect of uremia independent of its blood pressure-lowering effect, possibly because of antiinflammatory and antioxidative mechanisms.