The potential role of AT(1)-receptor blockade in the prevention and reversal of atherosclerosis.
The renin-angiotensin system may contribute to the development and progression of atherosclerosis both by increasing blood pressure and by direct effects on all phases of the atherogenic process. Genetic determinants of renin-angiotensin system activation, notably the DD genotype of angiotensin converting enzyme (ACE), are associated with an increased risk of cardiovascular events, as is increased plasma renin activity. In addition, angiotensin II has been shown to increase the uptake and oxidation of low density lipoprotein (LDL) by macrophages and endothelial cells. Angiotensin II also stimulates the production of interleukin 6 and activates the pro-inflammatory factor nuclear factor kappa(B), leading to expression of adhesion molecules and recruitment of monocytes and macrophages, and increases the production of pro-coagulatory factors. In animal experiments, treatment with ACE inhibitors or angiotensin AT(1)-receptor blockers has been shown to have anti-atherogenic effects. Studies with candesartan have shown that this agent produces a dose-dependent reduction in uptake of oxidised LDL by mouse macrophages in vitro, and reduces cholesterol accumulation and atherosclerosis development in the aorta of Watanabe rabbits. These effects were independent of changes in blood pressure. Such findings suggest that AT(1)-receptor blockers may be beneficial in reducing mortality and morbidity resulting from atherosclerotic disease, and are consistent with the findings from large outcome trials with ACE inhibitors in patients at risk of cardiovascular events.
Hypertension and Cardiovascular Research Clinic, VA Medical Center, Georgetown University, Washington DC 20422, USA.
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Papademetriou
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1