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(Circulation. 2002;106:2244.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Targeted Deletion of Angiotensin II Type 2 Receptor Caused Cardiac Rupture After Acute Myocardial Infarction

Sahoko Ichihara, MD, PhD; Takaaki Senbonmatsu, MD, PhD; Edward Price, Jr, MS; Toshihiro Ichiki, MD, PhD; F. Andrew Gaffney, MD; Tadashi Inagami, PhD

From the Departments of Biochemistry (S.I., T.S., E.P., T. Ichiki, T. Inagami) and Medicine (F.A.G.), Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Tadashi Inagami, PhD, Department of Biochemistry, Vanderbilt University School of Medicine, 663 Light Hall, 23rd at Pierce Ave, Nashville, TN 37232-0146. E-mail tadashi.inagami{at}vanderbilt.edu

Background— Accumulating evidence has suggested that the cardiac renin-angiotensin system is activated during the remodeling process after myocardial infarction (MI). Although 2 types of angiotensin II receptors (AT₁ and AT₂) are upregulated in the infarcted tissue, the contribution of AT₂ to the subsequent fibrogenetic phase of wound healing is less certain. This study was conducted to evaluate the role of AT₂ in wound healing after MI using an in vivo intervention study in mice with MI.

Methods and Results— We examined myocardial hypertrophy, cardiac fibrosis, and morphological evidence of fibrillar collagen accumulation at the infarcted and noninfarcted regions in male mice lacking the AT₂ receptor (Agtr2-/Y) and age-matched wild-type (WT) animals. Of the Agtr2-/Y mice, 63.6% died of cardiac rupture, whereas 23.5% of the WT mice died of the same cause within 1 week. The extent of fibrosis and that of collagen gene expression in Agtr2-/Y mice were significantly reduced compared with WT mice at 1 week after coronary ligation. Furthermore, MI resulted in a marked increase in the prostaglandin E₂ (PGE₂) level at 4 days after surgery in Agtr2-/Y mice. In WT mice, the PGE₂ level was also elevated after MI but to a significantly lesser extent than in Agtr2-/Y mice.

Conclusions— A chronic loss of AT₂ by gene targeting prevented the collagen deposition and caused cardiac rupture. The markedly elevated PGE₂ may be a mechanism that inhibits collagen synthesis in the infarcted region of Agtr2-/Y mice.

Key Words: angiotensin • collagen • myocardial infarction • prostaglandins • remodeling

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