This Article Full Text Full Text (PDF) All Versions of this Article: 110/3/317    most recent 01.CIR.0000135599.33787.CAv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mano, A. Articles by Matsubara, H. Search for Related Content PubMed PubMed Citation Articles by Mano, A. Articles by Matsubara, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Congestive ACE/Angiotension receptors Apoptosis

(Circulation. 2004;110:317-323.)
© 2004 American Heart Association, Inc.

Original Articles

Aldosterone Directly Induces Myocyte Apoptosis Through Calcineurin-Dependent Pathways

Akiko Mano, MD; Tetsuya Tatsumi, MD, PhD; Jun Shiraishi, MD, PhD; Natsuya Keira, MD, PhD; Tetsuya Nomura, MD; Mitsuo Takeda, MD; Susumu Nishikawa, MD; Satoshi Yamanaka, MD, PhD; Satoaki Matoba, MD, PhD; Miyuki Kobara, MD, PhD; Hideo Tanaka, MD, PhD; Takeshi Shirayama, MD, PhD; Tetsuo Takamatsu, MD, PhD; Yoshihisa Nozawa, PhD; Hiroaki Matsubara, MD, PhD

From the Departments of Cardiovascular Medicine and Pathology and Cell Regulation (H.T., T.T.), Kyoto Prefectural University School of Medicine, Kyoto, and Pharmacobioregulation Research Laboratory (Y.N.), Taiho Pharmaceutical Co. Ltd, Iinou, Japan.

Correspondence to Tetsuya Tatsumi, MD, PhD, Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail tatsumi{at}koto.kpu-m.ac.jp

Received January 21, 2004; revision received April 1, 2004; accepted April 5, 2004.

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 [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.

Key Words: angiotensin • apoptosis • heart failure

This article has been cited by other articles:

				D. S. De Silva, R. M. Wilson, C. Hutchinson, P. C. Ip, A. G. Garcia, S. Lancel, M. Ito, D. R. Pimentel, and F. Sam Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1983 - H1993. [Abstract] [Full Text] [PDF]

				W.-Q. Tan, J.-X. Wang, Z.-Q. Lin, Y.-R. Li, Y. Lin, and P.-F. Li Novel Cardiac Apoptotic Pathway: The Dephosphorylation of Apoptosis Repressor With Caspase Recruitment Domain by Calcineurin Circulation, November 25, 2008; 118(22): 2268 - 2276. [Abstract] [Full Text] [PDF]

				J. T. Mathew, H. Patni, A. N. Chaudhary, W. Liang, A. Gupta, P. N. Chander, G. Ding, and P. C. Singhal Aldosterone induces mesangial cell apoptosis both in vivo and in vitro Am J Physiol Renal Physiol, July 1, 2008; 295(1): F73 - F81. [Abstract] [Full Text] [PDF]

				Y. Iwazu, S. Muto, G. Fujisawa, E. Nakazawa, K. Okada, S. Ishibashi, and E. Kusano Spironolactone Suppresses Peritubular Capillary Loss and Prevents Deoxycorticosterone Acetate/Salt-Induced Tubulointerstitial Fibrosis Hypertension, March 1, 2008; 51(3): 749 - 754. [Abstract] [Full Text] [PDF]

				M. Colella, F. Grisan, V. Robert, J. D. Turner, A. P. Thomas, and T. Pozzan Ca2+ oscillation frequency decoding in cardiac cell hypertrophy: Role of calcineurin/NFAT as Ca2+ signal integrators PNAS, February 26, 2008; 105(8): 2859 - 2864. [Abstract] [Full Text] [PDF]

				H. Patni, J. T. Mathew, L. Luan, N. Franki, P. N. Chander, and P. C. Singhal Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1065 - F1071. [Abstract] [Full Text] [PDF]

				Q. Liu, B. J. Wilkins, Y. J. Lee, H. Ichijo, and J. D. Molkentin Direct Interaction and Reciprocal Regulation between ASK1 and Calcineurin-NFAT Control Cardiomyocyte Death and Growth Mol. Cell. Biol., May 15, 2006; 26(10): 3785 - 3797. [Abstract] [Full Text] [PDF]

				M. Yamamuro, M. Yoshimura, M. Nakayama, K. Abe, M. Shono, S. Suzuki, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Direct Effects of Aldosterone on Cardiomyocytes in the Presence of Normal and Elevated Extracellular Sodium Endocrinology, March 1, 2006; 147(3): 1314 - 1321. [Abstract] [Full Text] [PDF]

				M. K. Rude, T.-A. S. Duhaney, G. M. Kuster, S. Judge, J. Heo, W. S. Colucci, D. A. Siwik, and F. Sam Aldosterone Stimulates Matrix Metalloproteinases and Reactive Oxygen Species in Adult Rat Ventricular Cardiomyocytes Hypertension, September 1, 2005; 46(3): 555 - 561. [Abstract] [Full Text] [PDF]

				A. S. Mihailidou Nongenomic Cardiovascular Actions of Aldosterone: A Receptor for All Seasons? Endocrinology, March 1, 2005; 146(3): 971 - 972. [Full Text] [PDF]