Abstract 1552: Effects of ACE Inhibitors and Angiotensin Receptor Blockers on Vascular Oxidative Stress and Atherogenesis Independent of AT1 Receptor Activation?
The angiotensin II type 1 (AT1) receptor is involved in the pathogenesis of atherosclerosis. The involvement of the bradykinin system in the effects of ACE inhibitors (ACE-I) and potential pleiotropic effects of angiotensin receptor blockers (ARB) and their contribution to the beneficial therapeutic effects of these agents remain unclear.
Methods and Results: Apolipoprotein E-deficent (ApoE−/ −) mice and homozygous double-knockout animals deficient of ApoE and the AT1A receptor (ApoE−/ −AT1−/ − mice) were fed a high-cholesterol diet for 7 weeks. Vascular oxidative stress (L-012 chemiluminescence), atherosclerotic lesion formation in the aortic root (oil red O staining), and endothelial dysfunction of isolated aortic segments were evident in ApoE−/ − mice, but were markedly reduced in double-knockout animals. Systolic blood pressure was significantly lower in ApoE−/ −AT1−/ − mice as compared with ApoE−/ − animals (tail-cuff measurements). Oral treatment of cholesterol-fed ApoE−/ −AT1−/ − mice with either the ACE-I ramipril or the ARB telmisartan did not result in a significant further reduction of systolic blood pressure. Endothelium-dependent vasodilation and aortic reactive oxygen species release were identical in double-knockout animals treated with placebo, ramipril, or telmisartan. Compared with placebo-treated ApoE−/ −AT1−/ − mice, atherosclerotic lesion formation was identical in double-knockout animals treated with the ARB, but was significantly increased in those treated with the ACE-I. There were no significant differences between the groups concerning plasma renin activities and aldosterone concentrations. Chronic AT2 receptor inhibition with PD123319 significantly increased plaque formation in ApoE−/ −AT1−/ − mice but had no significant effect on endothelial function.
Conclusions: Genetic disruption of the AT1A receptor reduces oxidative stress and atherogenesis in ApoE−/ − mice. The data from our model provide no evidence for pleiotropic effects of ARBs and the involvement of the bradykinin system in the effects of ACE inhibitors on vascular oxidative stress, endothelial dysfunction, and atherosclerosis. Diminished AT2 receptor activation may contribute to the development of atherosclerosis.