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Circulation. 2004 Jul 20;110(3):317-23. Epub 2004 Jul 12.

Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways.

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Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Japan.

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Abstract

BACKGROUND:

Aldosterone has recently attracted considerable attention for its involvement in the pathophysiology of heart failure, in which apoptotic cell loss plays a critical role. This study examined whether aldosterone directly induces myocyte apoptosis via its specific receptors.

METHODS AND RESULTS:

Neonatal rat cardiac myocytes were exposed to aldosterone (10(-8) to 10(-5) mol/L). Nuclear staining with Hoechst 33258 showed that aldosterone induced myocyte apoptosis in a dose- and time-dependent fashion. Treatment of myocytes with 10(-5) mol/L aldosterone significantly increased the percentage of apoptosis (15.5+/-1.4%) compared with serum-deprived control (7.3+/-0.6%). Radio ligand binding assay revealed the existence of plasma membrane receptor with high affinity (K(d), 0.2 nmol/L) for aldosterone in cardiac myocytes but not in fibroblasts. Aldosterone rapidly (approximately 30 seconds) mobilized [Ca2+]i that was blocked by neomycin. Aldosterone induced dephosphorylation of the proapoptotic protein Bad, enhancement of mitochondrial permeability transition, decrease in mitochondrial membrane potential, and release of cytochrome c from the mitochondria into the cytosol with concomitant activation of caspase-3. These effects of aldosterone were inhibited by concurrent treatment with either an L-type Ca2+ channel antagonist, nifedipine, or inhibitors for the Ca2+-dependent phosphatase calcineurin, cyclosporin A and FK506.

CONCLUSIONS:

The present study demonstrates for the first time that the specific plasma membrane receptor (coupled with phospholipase C) for aldosterone is present on cardiac myocytes and that aldosterone accelerates the mitochondrial apoptotic pathway through activation of calcineurin and dephosphorylation of Bad, suggesting that the proapoptotic action of aldosterone may directly contribute to the progression of heart failure.

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