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(Circulation. 2005;111:2157-2164.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction

Jun Katada, PhD; Tomomi Meguro, MD; Hitomi Saito, BSc; Akira Ohashi, MD; Toshihisa Anzai, MD; Satoshi Ogawa, MD; Tsutomu Yoshikawa, MD

From the Pfizer-KEIO Research Laboratory (J.K., T.M., H.S., A.O.) and Cardiopulmonary Division, Keio University School of Medicine (S.O., T.A., T.Y.), Tokyo, Japan.

Correspondence to Jun Katada, PhD, Research Park 2N4, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail katada{at}kt.rim.or.jp

Received July 2, 2004; revision received December 16, 2004; accepted December 21, 2004.

Background— The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)–dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II–independent remodeling is unclear.

Methods and Results— Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor–knockout (AT_1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT_1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT_1A-KO mice. In AT_1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized.

Conclusions— Our results indicate that genetic blockade of AT_1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II–independent mechanisms.

Key Words: myocardial infarction • remodeling • angiotensin

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