Hypercholesterolemia is associated with enhanced angiotensin AT(1)-receptor expression

Low-density lipoprotein increases the AT(1)-receptor gene expression in vascular smooth muscle cells. To elucidate whether elevated cholesterol serum levels upregulate the AT(1) receptor and its functional response to angiotensin II in vivo, we compared 1) the vasoconstrictive effect of angiotensin II and 2) the level of expression of the vascular AT(1) receptor in aortas of normocholesterolemic and hypercholesterolemic rabbits. Contraction experiments on isolated aortic rings showed that the angiotensin II-induced vasoconstriction was increased in hypercholesterolemic New Zealand White rabbits compared with normocholesterolemic New Zealand White rabbits. This difference in the angiotensin II-induced vasoconstriction was caused by a twofold increase in the density of cell surface AT(1) receptors in hypercholesterolemic rabbits, as assessed by radioligand binding assays. The enhanced expression of AT(1) receptors on the surface of these vascular cells was caused by elevated steady-state levels of the AT(1)-receptor mRNA to 220 +/- 35% in aortas excised from hypercholesterolemic rabbits compared with levels in aortas from normocholesterolemic rabbits, as measured by Northern blot analysis. These data indicate that hypercholesterolemia is associated with upregulation of expression and function of vascular AT(1) receptors in vivo. This suggests a novel mechanism by which hypercholesterolemia could be involved in the onset and progression of chronic vascular diseases such as hypertension and arteriosclerosis if the phenomenon is confirmed in humans.