Published online before print November 25, 2002, doi: 10.1161/01.HYP.0000050101.90932.14
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(Hypertension. 2003;41:99.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Cardiac Angiotensin II Type 2 Receptor Activates the Kinin/NO System and Inhibits Fibrosis
From the First Department of Internal Medicine (S.K., T.I., H.S., H. Matsuura, K.C.) and Clinical Laboratory Medicine (R.O., T.O., M.K.), Second Department of Physiology (Y.T.), Hiroshima University School of Medicine, Hiroshima, Japan; and Internal Medicine II, Kansai Medical University (O.I., K.A., H. Matsubara), Osaka, Japan.
Correspondence to Ryoji Ozono, MD, Department of Clinical Laboratory Medicine, Hiroshima University Faculty of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan 734-8551. E-mail ozono{at}hiroshima-u.ac.jp
We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT2 receptors in cardiomyocytes attenuates Ang II–induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT2 receptor relative to AT1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by 
45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (2.6-fold, P<0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B2 receptors were present in fibroblasts. These results suggest that stimulation of AT2 receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting.
Key Words: receptors, angiotensin II • kinins • mice • fibrosis • hypertrophy
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