Published Online
on April 25, 2005

A more recent version of this article appeared on May 3, 2005

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Submitted on July 2, 2004
Revised on December 16, 2004
Accepted on December 21, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: katada{at}kt.rim.or.jp.

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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