Increased Angiotensin II Type 1 Receptor Expression in Hypercholesterolemic Atherosclerosis in Rabbits

From the Departments of Medicine (B.C.Y., J.L.M.), Physiology (M.I.P., D.M., H.M., L.S., J.L.M.), and Pediatrics (P.M.), University of Florida, College of Medicine, and the VA Medical Center (J.L.M.), Gainesville, Fla.

Correspondence to J.L. Mehta, MD, PhD, Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd, PO Box 100277 JHMHC, Gainesville, FL 32610. E-mail jmehta{at}ufl.edu

Abstract—Angiotensin II (Ang II) promotes vascular smooth muscle growth and may be involved in the initiation and progression of atherosclerosis. To examine whether Ang II receptor expression in vascular tissues is altered in atherosclerosis, male New Zealand White rabbits were fed a high-cholesterol diet (1% cholesterol+4% coconut oil mixed with regular chow; hypercholesterolemic group, n=12) or regular chow (control group, n=8) for 10 weeks. At the end of this period, the serum cholesterol level in the rabbits fed the high-cholesterol diet was higher than that in the control group (3616±144 versus 30±1 mg/dL, P<0.001). There was no atherosclerosis in the aortas of the control group, whereas 51±6% of the aorta was covered with atherosclerosis in the hypercholesterolemic group. Total Ang II receptor expression in the atherosclerotic aortic tissues was increased 5-fold in the hypercholesterolemic rabbits (292±28 versus 51±32 fmol/mg tissue, mean±SE, P<0.001), and the increased Ang II receptor expression was entirely due to enhanced Ang II type 1 (AT₁) receptor expression (289±38 versus 38±18 fmol/mg, P<0.001), as Ang II type 2 receptor expression was unaltered (7±5 versus 3±2 fmol/mg, P=NS). AT₁ receptors were localized primarily in the media and to some extent in the intima of the atherosclerotic aorta, as determined by immunohistochemistry with specific monoclonal and polyclonal AT₁ receptor antibodies. Increased synthesis of AT₁ receptor mRNA in atherosclerotic tissues was confirmed by reverse transcription–polymerase chain reaction. To evaluate the functional significance of increased AT₁ receptor expression, the constrictor response of aortic rings to Ang II was examined and found to be markedly enhanced in atherosclerotic aortic rings (P<0.01 versus control aortic rings). The endothelium-dependent relaxation of aortic rings from hypercholesterolemic rabbits was markedly attenuated (P<0.001). This study shows that hypercholesterolemia in rabbits results in atherosclerosis, loss of endothelium-dependent relaxation, and increased Ang II receptor (entirely AT₁ receptor) expression in aortic tissues, which may result in altered vasoreactivity.

Key Words: aorta • atherosclerosis • angiotensin II • endothelium • hypercholesterolemia

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