| First Author | Wassmann S | Year | 2004 |
| Journal | Circulation | Volume | 110 |
| Issue | 19 | Pages | 3062-7 |
| PubMed ID | 15277329 | Mgi Jnum | J:103721 |
| Mgi Id | MGI:3610652 | Doi | 10.1161/01.CIR.0000137970.47771.AF |
| Citation | Wassmann S, et al. (2004) Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice. Circulation 110(19):3062-7 |
| abstractText | 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. |
