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(Circulation. 2005;112:3328-3336.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to Virna L. Sales, MD, Department of Cardiac Surgery, Children’s Hospital Boston, 300 Longwood Ave, Bader 279, Boston, MA 02115. E-mail virna.sales{at}childrens.harvard.edu

Received February 8, 2005; revision received August 1, 2005; accepted September 12, 2005.

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.

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