Published online before print April 22, 2004, doi: 10.1161/01.RES.0000129179.66631.00
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Cellular Biology |
Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits ß-Agonist-Induced Cardiac Apoptosis
From the Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio.
Correspondence to Dr Evangelia G. Kranias, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575. E-mail Litsa.Kranias{at}uc.edu
Activation of the sympathetic nervous system is a common compensatory feature in heart failure, but sustained ß-adrenergic activation induces cardiomyocyte death, leading to cardiac remodeling and dysfunction. In mouse cardiomyocytes, we recently reported that prolonged exposure to ß-agonists is associated with transient increases in expression and phosphorylation of a small heat-shock protein, Hsp20. To determine the functional significance of Hsp20, we overexpressed this protein and its constitutively phosphorylated (S16D) or nonphosphorylated (S16A) mutant in adult rat cardiomyocytes. Hsp20 protected cardiomyocytes from apoptosis triggered by activation of the cAMP-PKA pathway, as indicated by decreases in the number of pyknotic nuclei, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling, and DNA laddering, which were associated with inhibition of caspase-3 activity. These protective effects were further increased by the constitutively phosphorylated Hsp20 mutant (S16D), which conferred full protection from apoptosis. In contrast, the nonphosphorylatable mutant (S16A) exhibited no antiapoptotic properties. Immunostaining studies and immunoprecipitations with Hsp20 or actin antibodies demonstrated that Hsp20 translocated to cytoskeleton and associated with actin on isoproterenol stimulation. These findings suggest that Hsp20 and its phosphorylation at Ser16 may provide cardioprotection against ß-agonist-induced apoptosis. Thus, Hsp20 may represent a novel therapeutic target in the treatment of heart failure.
Key Words: apoptosis • ß-agonist • small heat-shock protein • cardiomyocyte • cytoskeleton
This article has been cited by other articles:
 |
|
 |
|
  R. Granata, L. Trovato, M. P. Gallo, S. Destefanis, F. Settanni, F. Scarlatti, A. Brero, R. Ramella, M. Volante, J. Isgaard, et al. Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart Cardiovasc Res, July 15, 2009; 83(2): 303 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-P. Ren, J. Wu, X. Wang, M. A. Sartor, J. Qian, K. Jones, P. Nicolaou, T. J. Pritchard, and G.-C. Fan MicroRNA-320 Is Involved in the Regulation of Cardiac Ischemia/Reperfusion Injury by Targeting Heat-Shock Protein 20 Circulation, May 5, 2009; 119(17): 2357 - 2366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Waggoner, K. S. Ginsburg, B. Mitton, K. Haghighi, J. Robbins, D. M. Bers, and E. G. Kranias Phospholamban overexpression in rabbit ventricular myocytes does not alter sarcoplasmic reticulum Ca transport Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H698 - H703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Nicolaou, R. Knoll, K. Haghighi, G.-C. Fan, G. W. Dorn II, G. Hasenfuss, and E. G. Kranias Human Mutation in the Anti-apoptotic Heat Shock Protein 20 Abrogates Its Cardioprotective Effects J. Biol. Chem., November 28, 2008; 283(48): 33465 - 33471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-C. Fan, X. Zhou, X. Wang, G. Song, J. Qian, P. Nicolaou, G. Chen, X. Ren, and E. G. Kranias Heat Shock Protein 20 Interacting With Phosphorylated Akt Reduces Doxorubicin-Triggered Oxidative Stress and Cardiotoxicity Circ. Res., November 21, 2008; 103(11): 1270 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shi, L. Yu, C. Chiu, Y. Sun, J. Chen, G. Khitrov, M. Merkenschlager, L. B. Holzman, W. Zhang, P. Mundel, et al. Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis J. Am. Soc. Nephrol., November 1, 2008; 19(11): 2159 - 2169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chen, X. Zhou, P. Nicolaou, P. Rodriguez, G. Song, B. Mitton, A. Pathak, A. Zachariah, G.-C. Fan, G. W. Dorn II, et al. A human polymorphism of protein phosphatase-1 inhibitor-1 is associated with attenuated contractile response of cardiomyocytes to {beta}-adrenergic stimulation FASEB J, June 1, 2008; 22(6): 1790 - 1796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B E Cross, H M O'Dea, and D J MacPhee Expression of small heat shock-related protein 20 (HSP20) in rat myometrium is markedly decreased during late pregnancy and labour Reproduction, April 1, 2007; 133(4): 807 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rodriguez, B. Mitton, J. R. Waggoner, and E. G. Kranias Identification of a Novel Phosphorylation Site in Protein Phosphatase Inhibitor-1 as a Negative Regulator of Cardiac Function J. Biol. Chem., December 15, 2006; 281(50): 38599 - 38608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-C. Fan, Q. Yuan, G. Song, Y. Wang, G. Chen, J. Qian, X. Zhou, Y. J. Lee, M. Ashraf, and E. G. Kranias Small Heat-Shock Protein Hsp20 Attenuates {beta}-Agonist-Mediated Cardiac Remodeling Through Apoptosis Signal-Regulating Kinase 1 Circ. Res., November 24, 2006; 99(11): 1233 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Chen, J.-B. Liu, K. M. Horak, H. Zheng, A. R.K. Kumarapeli, J. Li, F. Li, A. M. Gerdes, E. F. Wawrousek, and X. Wang Intrasarcoplasmic Amyloidosis Impairs Proteolytic Function of Proteasomes in Cardiomyocytes by Compromising Substrate Uptake Circ. Res., November 11, 2005; 97(10): 1018 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lucchinetti, R. da Silva, T. Pasch, M. C. Schaub, and M. Zaugg Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning Br. J. Anaesth., August 1, 2005; 95(2): 140 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. De Celle, F. Vanrobaeys, P. Lijnen, W. M. Blankesteijn, S. Heeneman, J. Van Beeumen, B. Devreese, J. F. M Smits, and B. J. A Janssen Alterations in mouse cardiac proteome after in vivo myocardial infarction: permanent ischaemia versus ischaemia-reperfusion Exp Physiol, July 1, 2005; 90(4): 593 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-C. Fan, X. Ren, J. Qian, Q. Yuan, P. Nicolaou, Y. Wang, W. K. Jones, G. Chu, and E. G. Kranias Novel Cardioprotective Role of a Small Heat-Shock Protein, Hsp20, Against Ischemia/Reperfusion Injury Circulation, April 12, 2005; 111(14): 1792 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, H.-Y. Zhang, K. Pavlish, and J. N. Benoit Effects of chronic portal hypertension on small heat-shock proteins in mesenteric arteries Am J Physiol Gastrointest Liver Physiol, April 1, 2005; 288(4): G616 - G620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. da Silva, E. Lucchinetti, T. Pasch, M. C. Schaub, and M. Zaugg Ischemic but not pharmacological preconditioning elicits a gene expression profile similar to unprotected myocardium Physiol Genomics, December 15, 2004; 20(1): 117 - 130. [Abstract] [Full Text] [PDF]
|
|