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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1080.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of the Renin-Angiotensin System Abolishes the Proatherogenic Effect of Uremia in Apolipoprotein E-Deficient Mice

Susanne Bro; Christoph J. Binder; Joseph L. Witztum; Klaus Olgaard; Lars B. Nielsen

From the Departments of Nephrology (S.B., K.O.), Clinical Biochemistry (S.B., L.B.N.), Rigshospitalet, and the Department of Biomedical Sciences (L.B.N.), University of Copenhagen, Denmark; the Institute of Medical and Chemical Laboratory Diagnostics (C.J.B.), Medical University of Vienna, Austria; and the Division of Endocrinology & Metabolism, Department of Medicine (C.J.B., J.L.W.), University of California, San Diego (UCSD), La Jolla, Calif.

Correspondence to Susanne Bro, MD, PhD, Dept. of Nephrology P 2131, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail susannebro{at}dadlnet.dk

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.

Uremia markedly accelerates atherosclerosis in apolipoprotein E-deficient (apoE^–/–) mice. RAS inhibition, but not blood pressure reduction with a non-RAS-dependent vasodilator, abolished the proatherogenic effect of uremia in apoE^–/– mice, possibly because of antiinflammatory or antioxidative mechanisms.

Key Words: renal failure • atherosclerosis • blood pressure • oxidized low density lipoprotein antibodies • ICAM-1 • VCAM-1 • angiotensin converting enzyme inhibitor • angiotensin II receptor antagonist

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