Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways

Abstract

Background: Aldosterone has recently attracted considerable attention in the pathophysiology of heart failure, in which apoptotic cell loss plays a critical role. This study examined whether aldosterone directly induces myocyte apoptosis. Methods and Results: Neonatal rat cardiac myocytes were exposed to aldosterone. Nuclear staining with Hoechst 33258 showed that aldosterone induced myocyte apoptosis in a dose- and time-dependent fashion. 10 −5 mol/L aldosterone significantly increased myocyte apoptosis compared with serum-deprived control. Radioligand binding assay revealed the existence of plasma membrane receptor with high affinity for aldosterone in cardiac myocytes. Aldosterone rapidly mobilized [Ca 2+] 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 a L-type Ca 2+ channel antagonist, nifedipine, or inhibitors for the Ca 2+-dependent phosphatase calcineurin, cyclosporin A and FK506. Conclusion: The present study demonstrates for the first time that 1) the specific plasma membrane receptor for aldosterone is present on cardiac myocytes, and 2) 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.