Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice

Article

关键词: CONVERTING-ENZYME-INHIBITOR;    CORONARY-ARTERY-DISEASE;    ANGIOTENSIN-II;    RENIN-ANGIOTENSIN;    OXIDATIVE STRESS;    CARDIOVASCULAR EVENTS;    BLOOD-PRESSURE;    OXIDASE;    HYPERCHOLESTEROLEMIA;    AT(1)-RECEPTOR;   

DOI  :  10.1161/01.CIR.0000137970.47771.AF

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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