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Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice

¹Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; ²Department of Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina 29208; and ³Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229

Submitted 17 April 2003 ; accepted in final form 14 July 2003

The angiotensin II type 2 (AT₂) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological 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 (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (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 revealed 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, which implies a dose-response relationship. AT₂ overexpression was also directly associated with the increase of phosphorylated protein levels of PKC-, PKC-, and p70S6 kinase. These data demonstrate that ventricular myocyte-specific expression of AT₂ receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.

myosin light-chain promoter; cardiac disease; myocyte

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