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(Circulation. 2004;110:3849-3857.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Hypercholesterolemia Stimulates Angiotensin Peptide Synthesis and Contributes to Atherosclerosis Through the AT_1A Receptor

Alan Daugherty, PhD, DSc; Debra L. Rateri, BS; Hong Lu, PhD; Tadashi Inagami, PhD; Lisa A. Cassis, PhD

From the Division of Cardiovascular Medicine (A.D., D.L.R., H.L.) and the Graduate Center for Nutritional Sciences (A.D., L.A.C.), University of Kentucky, Lexington; and the Department of Biochemistry, Vanderbilt University, Nashville, Tenn (T.I.).

Correspondence to Alan Daugherty, Wethington Building, Room 521, University of Kentucky, Lexington, KY 40536-0200. E-mail alan.daugherty{at}uky.edu

Received September 26, 2004; revision received September 26, 2004; accepted October 21, 2004.

Background— Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT₁ receptors or AT_1A receptor deficiency. However, the mechanism underlying the pronounced responses to angiotensin II (Ang II) antagonism has not been determined. We hypothesized that hypercholesterolemia stimulates the production of angiotensin peptides to provide a rationale for the profound effect of AT_1A receptor deficiency on atherogenesis.

Methods and Results— Atherosclerotic lesions were analyzed in LDL receptor–deficient mice. Immunocytochemical analysis demonstrated that atherosclerotic lesions contained all the components of the conventional pathway for Ang II synthesis. AT_1A receptor deficiency caused a marked decrease in atherosclerotic lesion size in both the aortic root and arch of male and female mice, without a discernible effect on composition. AT_1A receptor deficiency–induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT₂ receptor mRNA expression was not altered in AT_1A receptor–deficient mice, and AT₂ receptor deficiency had no effect on lesion area or cellular composition. Hypercholesterolemia greatly augmented the systemic renin-angiotensin system, as demonstrated by large increases in plasma concentrations of angiotensinogen and angiotensin peptides (Ang II, III, IV, and 4–8). These increases were ablated in hypercholesterolemic AT_1A receptor–deficient mice.

Conclusions— AT_1A receptor deficiency had a striking effect in reducing hypercholesterolemia-induced atherosclerosis in LDL receptor–negative mice. Hypercholesterolemia was associated with increased systemic angiotensinogen and angiotensin peptides, which were reduced in AT_1A receptor–deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT_1A receptor deficiency in reducing atherosclerosis.

Key Words: atherosclerosis • blood pressure • angiotensin • hypercholesterolemia

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