on July 26, 2004
Published online before print July 26, 2004, doi: 10.1161/01.CIR.0000137970.47771.AF
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Submitted on December 16, 2003
From the Klinik für Innere Medizin III (S.W., T.C., M.B., G.N.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Aventis Pharma Deutschland (M.v.E.), Cardiovascular Disease Group, Frankfurt/Main, Germany; and Institut für Kardiovaskuläre Physiologie (I.F.), Johann W. Goethe-University, Frankfurt/Main, Germany. * To whom correspondence should be addressed. E-mail: nickenig{at}med-in.uni-sb.de.
Background--Angiotensin II type 1 (AT1) receptor activation is potentially involved in the multifactorial pathogenesis of atherosclerosis. Methods and Results--Apolipoprotein E-deficient (ApoE-/-) mice were crossed with AT1A receptor-deficient (AT1-/-) mice to obtain homozygous double-knockout animals (ApoE-/--AT1-/- mice). Wild-type (C57BL/6J), ApoE-/-, AT1-/-, and ApoE-/--AT1-/- mice were fed a high-cholesterol diet for 7 weeks. In contrast to wild-type and AT1-/- mice, this treatment led to severe atherosclerotic lesion formation in the aortic sinus and the aorta (oil red O staining) and to an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments) in ApoE-/- mice. In the age-matched ApoE-/--AT1-/- littermates, development of diet-induced endothelial dysfunction and atherosclerotic lesion formation was profoundly inhibited. Concomitantly, aortic release of superoxide radicals was increased 2-fold in ApoE-/- mice compared with wild-type animals, whereas aortic superoxide production was normalized in ApoE-/--AT1-/- mice (L-012 chemiluminescence). There were no significant differences in plasma cholesterol levels between ApoE-/- and ApoE-/--AT1-/- animals. Systolic blood pressure was significantly lower in ApoE-/--AT1-/- animals than in ApoE-/- mice (tail-cuff measurements). Oral treatment of ApoE-/- mice with either hydralazine or irbesartan reduced systolic blood pressure to the same level; however, only AT1 receptor antagonist treatment reduced atherosclerotic lesion formation and improved endothelial function. Conclusions--Genetic disruption of the AT1A receptor leads to inhibition of vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation in ApoE-/- mice irrespective of blood pressure and plasma cholesterol levels. These results indicate a fundamental role of AT1 receptor activation in atherogenesis.
Revised on May 19, 2004
Accepted on June 10, 2004
Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice
Sven Wassmann MD,
Key words: hypercholesterolemia • angiotensin • endothelium • atherosclerosis • free radicals
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