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Am J Physiol Heart Circ Physiol (July 17, 2003). doi:10.1152/ajpheart.00361.2003
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Submitted on April 17, 2003
Accepted on July 14, 2003

Ventricular-Specific Expression of Angiotensin II Type 2 Receptor Causes Dilated Cardiomyopathy and Heart Failure in Transgenic Mice

Xinhua Yan*, Robert L. Price, Masaharu Nakayama, Kenta Ito, Adam J. Schuldt, Warren J. Manning, Atsushi Sanbe, Thomas K. Borg, Jeffrey Robbins, and Beverly H. Lorell

* To whom correspondence should be addressed. E-mail: xyan{at}caregroup.harvard.edu.

The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle (LV) in heart failure, but its pathophysiologic roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light chain (MLC2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo LV systolic pressure and peak +dP/dt were depressed, while LV diastolic pressure was elevated (p<0.05). Echocardiography showed severely depressed LV fractional shortening, increased systolic and diastolic dimensions, and wall thinning (p<0.05). Confocal and electron microscopy studies demonstrated an increase in the size of myocytes and interstitial spaces as well as an increase in interstitial collagen, disruption of the Z-band, and changes in cytochrome C localization. The changes were most prominent in the highest expressing TG line, implying a dose response relationship. AT2 overexpression was also directly associated with the increase of phosphorylated protein levels of PKC{alpha},PKC{beta},and p70 S6K. These data demonstrate that ventricular myocyte-specific expression of AT2 receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.




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