title: Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways.
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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mano
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Jun
authors.initials: J
authors.lastname: Shiraishi
authors.forename: Natsuya
authors.initials: N
authors.lastname: Keira
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nomura
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Takeda
authors.forename: Susumu
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Hideo
authors.initials: H
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shirayama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takamatsu
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000032:analysis; D018161:Receptors, Mineralocorticoid / Q000032:analysis; D015398:Signal Transduction; D051025:bcl-Associated Death Protein
chemical_list: C494821:Bad protein, rat; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011956:Receptors, Cell Surface; D018161:Receptors, Mineralocorticoid; D051025:bcl-Associated Death Protein; D000450:Aldosterone; D045304:Cytochromes c; D019703:Calcineurin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium