Aldosterone Directly Induces Myocyte Apoptosis Through Calcineurin-Dependent Pathways
| Autor: | Tetsuya Nomura, Miyuki Kobara, Tetsuya Tatsumi, Hiroaki Matsubara, Satoaki Matoba, Jun Shiraishi, Tetsuo Takamatsu, Takeshi Shirayama, Mitsuo Takeda, Akiko Mano, Satoshi Yamanaka, Susumu Nishikawa, Natsuya Keira, Yoshihisa Nozawa, Hideo Tanaka |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Calcineurin Inhibitors Apoptosis Receptors Cell Surface Biology Mitochondrial Membrane Transport Proteins Ion Channels Membrane Potentials Dephosphorylation chemistry.chemical_compound Physiology (medical) Cyclosporin a Internal medicine Renin–angiotensin system medicine Animals Myocyte Myocytes Cardiac Enzyme Inhibitors Rats Wistar Aldosterone Caspase 3 Mitochondrial Permeability Transition Pore Calcineurin Cytochromes c Calcium Channel Blockers Mitochondria Rats Receptors Mineralocorticoid Endocrinology Mitochondrial permeability transition pore chemistry Caspases Calcium bcl-Associated Death Protein Signal transduction Carrier Proteins Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Circulation. 110:317-323 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | 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 (≈30 seconds) 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 an L-type Ca 2+ channel antagonist, nifedipine, or inhibitors for the Ca 2+ -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. |
| Databáze: | OpenAIRE |
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