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

Abstract

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. (Circulation. 2005;111:2157-2164.)

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

“…In view of the tissue-specific activation of myocardial aldosterone, Silvestre et al have already reported that MI raises aldosterone synthase (CYP11B2) mRNA by 2.0-fold and the aldosterone level by 3.7-fold in rats (39). More recently, Katada et al have reported that gene expression levels of aldosterone synthase and cardiac aldosterone content are both elevated in MI hearts even in angiotensin II type 1A receptor-knockout mice (40). In various epithelial cells, expression of 11β-HSD2 converts endogenous glucocorticoids to their receptor-inactive 11-keto analogs, thereby conferring aldosterone selectivity on MR (41).…”

Cardioprotective Effects of Eplerenone in the Rat Heart

“…This does not exclude the possibility that local production of aldosterone becomes an important determinant of cardiac aldosterone levels under pathological conditions. 29 …”

Aldosterone-and-Salt-Induced Cardiac Fibrosis Is Independent from Angiotensin II Type 1a Receptor Signaling in Mice

“…Elevation of BP also might not be necessary for Ald-NaCl-induced cardiac fibrosis, because in the present study, AT1aR-KO treated with Ald-NaCl showed an SBP comparable to that of Wt treated with NaCl alone, which showed much milder cardiac fibrosis. Katada et al recently reported the importance of aldosterone on cardiac remodeling after myocardial infarction in AT1aR-KO (25). In their report, induction of myocardial infarction increased the production of aldosterone in the hearts of AT1aR-KO, and spironolactone prevented the cardiac fibrosis with the reduction of gene expression of collagens and natriuretic peptides (25).…”

“…Katada et al recently reported the importance of aldosterone on cardiac remodeling after myocardial infarction in AT1aR-KO (25). In their report, induction of myocardial infarction increased the production of aldosterone in the hearts of AT1aR-KO, and spironolactone prevented the cardiac fibrosis with the reduction of gene expression of collagens and natriuretic peptides (25).…”