Published Online
on November 14, 2005

A more recent version of this article appeared on November 22, 2005

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Submitted on February 8, 2005
Revised on August 1, 2005
Accepted on September 12, 2005

Angiotensin Type 2 Receptor Is Expressed in Murine Atherosclerotic Lesions and Modulates Lesion Evolution

Virna L. Sales MD^*, Galina K. Sukhova PhD, Marco A. Lopez-Ilasaca MD, PhD, Peter Libby MD, Victor J. Dzau MD, and Richard E. Pratt PhD

From the Cardiovascular Division (V.L.S., M.A.L.-I., V.J.D., R.E.P.) and Donald W. Reynolds Cardiovascular Clinical Research Center (G.K.S., P.L.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Dr Sales is now at the Department of Cardiac Surgery, Children’s Hospital Boston, Harvard Medical School, Boston, Mass; Dr Dzau is now at the Office of the Chancellor, Duke University Medical Center, Durham, NC.

^* To whom correspondence should be addressed. E-mail: virna.sales{at}childrens.harvard.edu.

Background--In the vasculature, the angiotensin type 2 (AT₂) receptor (AT₂R) exerts antiproliferative, antifibrotic, and proapoptotic effects. Normal adult animals have low AT₂R expression; however, vascular injury and exposure to proinflammatory cytokines augment AT₂R levels. We hypothesized that AT₂R expression increases during initiation and progression of atherosclerosis.

Methods and Results--Atherosclerotic lesions of apolipoprotein (Apo) E^-/- mice contained AT₂Rs, measured by real-time polymerase chain reaction and confirmed by immunohistochemistry. To test the consequences of this expression, male ApoE^-/-, angiotensin II type 2 receptor-deficient (Agtr2^-), and ApoE^-/-, wild-type (Agtr2⁺) mice consumed a high-cholesterol diet from 4 weeks of age. Ten weeks later, overall area and cellular composition of aortic arch lesions did not differ significantly among genotypes. After 16 weeks, ApoE^-/-/Agtr2⁺, but not ApoE^-/-/Agtr2^- mice had dramatic decreases in percent positive area of macrophages, smooth muscles, lipids, and collagen. Diminished bromodeoxyuridine incorporation and increased TUNEL staining accompanied these decreases.

Conclusions--Thus, loss of AT₂R during the evolution of atherosclerotic lesions augmented the extent of cellularity of atherosclerotic lesions, establishing AT₂R as a modulator of atherogenesis.

Key words: angiotensin • atherosclerosis • inflammation • receptors • renin

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