Regulation of the angiotensin AT1 receptor expression by hypercholesterolemia.

The AT1 receptor mediates most of the biological effects of angiotensin II and has therefore been implicated in the pathogenesis of hypertension as well as arteriosclerosis. Hypercholesterolemia is a prominent risk factor for the development of these cardiovascular diseases. Since experimental results from hyperlipidemic animal models suggested an interaction of the renin-angiotensin system and hypercholesterolemia, the effects of low-density lipoprotein (LDL) and hypercholesterolemia has recently been investigated in vitro and in vivo. LDL causes in cultured vascular smooth muscle cells an up-regulation of AT1 receptor gene expression which is followed by an enhanced functional response upon stimulation with angiotensin II. This effect is also evident in vivo, as assessed in hypercholesterolemic rabbits. The vascular AT1 receptor expression is increased approximately twofold in hypercholesterolemic rabbits in comparison to normocholesterolemic animals. This leads ultimately to an enhanced angiotensin II-induced vasoconstriction. Thus, hypercholesterolemia and elevated concentrations of LDL enhance AT1 receptor expression in the vasculature causing an enhanced biological effectiveness of the renin-angiotensin system. This interaction may explain that blockade of the renin-angiotensin system attenuates the progress of arteriosclerosis in the hypercholesterolemic organismen and indicates a pathophysiologically important role for the lipid-induced AT1 receptor up-regulation.