Stress (Heat Shock) Proteins

Molecular Chaperones in Cardiovascular Biology and Disease

From the Department of Internal Medicine and Integrative Biology Graduate Program, Molecular Cardiology Research Laboratories, The University of Texas Southwestern Medical Center, Dallas, Tex.

Correspondence to Ivor J. Benjamin, MD, Molecular Cardiology Research Laboratories and Integrative Biology Graduate Program, U.T. Southwestern Medical Center, Dallas, TX 75235-8573. E-mail benjamin{at}ryburn.swmed.edu

Abstract—How a cell responds to stress is a central problem in cardiovascular biology. Diverse physiological stresses (eg, heat, hemodynamics, mutant proteins, and oxidative injury) produce multiple changes in a cell that ultimately affect protein structures and function. Cells from different phyla initiate a cascade of events that engage essential proteins, the molecular chaperones, in decisions to repair or degrade damaged proteins as a defense strategy to ensure survival. Accumulative evidence indicates that molecular chaperones such as the heat shock family of stress proteins (HSPs) actively participate in an array of cellular processes, including cytoprotection. The versatility of the ubiquitous HSP family is further enhanced by stress-inducible regulatory networks, both at the transcriptional and posttranscriptional levels. In the present review, we discuss the regulation and function of HSP chaperones and their clinical significance in conditions such as cardiac hypertrophy, vascular wall injury, cardiac surgery, ischemic preconditioning, aging, and, conceivably, mutations in genes encoding contractile proteins and ion channels.

Key Words: stress protein • gene expression • molecular chaperone • transcription factor • vascular biology • aging • ischemia

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				S. P. Anderson, P. Howroyd, J. Liu, X. Qian, R. Bahnemann, C. Swanson, M.-K. Kwak, T. W. Kensler, and J. C. Corton The Transcriptional Response to a Peroxisome Proliferator-activated Receptor {alpha} Agonist Includes Increased Expression of Proteome Maintenance Genes J. Biol. Chem., December 10, 2004; 279(50): 52390 - 52398. [Abstract] [Full Text] [PDF]

				C.-L. Su, C.-P. Wu, S.-Y. Chen, B.-H. Kang, K.-L. Huang, and Y.-C. Lin Acclimatization to neurological decompression sickness in rabbits Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1214 - R1218. [Abstract] [Full Text] [PDF]

				K. Mandal, M. Jahangiri, M. Mukhin, J. Poloniecki, A. J. Camm, and Q. Xu Association of Anti-Heat Shock Protein 65 Antibodies With Development of Postoperative Atrial Fibrillation Circulation, October 26, 2004; 110(17): 2588 - 2590. [Abstract] [Full Text] [PDF]

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				T. M. Griffin, T. V. Valdez, and R. Mestril Radicicol activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1081 - H1088. [Abstract] [Full Text] [PDF]

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				G.-C. Fan, G. Chu, B. Mitton, Q. Song, Q. Yuan, and E. G. Kranias Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits {beta}-Agonist-Induced Cardiac Apoptosis Circ. Res., June 11, 2004; 94(11): 1474 - 1482. [Abstract] [Full Text] [PDF]

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				Y. Zou, W. Zhu, M. Sakamoto, Y. Qin, H. Akazawa, H. Toko, M. Mizukami, N. Takeda, T. Minamino, H. Takano, et al. Heat Shock Transcription Factor 1 Protects Cardiomyocytes From Ischemia/Reperfusion Injury Circulation, December 16, 2003; 108(24): 3024 - 3030. [Abstract] [Full Text] [PDF]

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