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      The role of heat shock proteins and co-chaperones in heart failure

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          Abstract

          <p class="first" id="d575625e195">The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by the <i>Stub1</i> gene) and BAG-3 (BCL2-associated athanogene 3). Here, we review their emerging roles in the maintenance of cardiomyocytes in human and experimental models of heart failure, including their roles in facilitating the removal of misfolded and degraded proteins, inhibiting apoptosis and maintaining the structural integrity of the sarcomere and regulation of nuclear receptors. Furthermore, we discuss emerging evidence of increased expression of extracellular HSP70, HSP90 and BAG-3 in heart failure, with complementary independent roles from intracellular functions with important therapeutic and diagnostic considerations. While our understanding of these major HSPs in heart failure is incomplete, there is a clear potential role for therapeutic modulation of HSPs in heart failure with important contextual considerations to counteract the imbalance of protein damage and endogenous protein quality control systems. </p><p id="d575625e200">This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’. </p>

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          Most cited references166

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          Molecular chaperones in cellular protein folding.

          F U Hartl (1996)
          The folding of many newly synthesized proteins in the cell depends on a set of conserved proteins known as molecular chaperones. These prevent the formation of misfolded protein structures, both under normal conditions and when cells are exposed to stresses such as high temperature. Significant progress has been made in the understanding of the ATP-dependent mechanisms used by the Hsp70 and chaperonin families of molecular chaperones, which can cooperate to assist in folding new polypeptide chains.
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            Is Open Access

            The Hsp70 and Hsp60 chaperone machines.

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              Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies.

              Cardiac hypertrophy can be defined as an increase in heart mass. Pathological cardiac hypertrophy (heart growth that occurs in settings of disease, e.g. hypertension) is a key risk factor for heart failure. Pathological hypertrophy is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. In contrast, physiological cardiac hypertrophy (heart growth that occurs in response to chronic exercise training, i.e. the 'athlete's heart') is reversible and is characterized by normal cardiac morphology (i.e. no fibrosis or apoptosis) and normal or enhanced cardiac function. Given that there are clear functional, structural, metabolic and molecular differences between pathological and physiological hypertrophy, a key question in cardiovascular medicine is whether mechanisms responsible for enhancing function of the athlete's heart can be exploited to benefit patients with pathological hypertrophy and heart failure. This review summarizes key experimental findings that have contributed to our understanding of pathological and physiological heart growth. In particular, we focus on signaling pathways that play a causal role in the development of pathological and physiological hypertrophy. We discuss molecular mechanisms associated with features of cardiac hypertrophy, including protein synthesis, sarcomeric organization, fibrosis, cell death and energy metabolism and provide a summary of profiling studies that have examined genes, microRNAs and proteins that are differentially expressed in models of pathological and physiological hypertrophy. How gender and sex hormones affect cardiac hypertrophy is also discussed. Finally, we explore how knowledge of molecular mechanisms underlying pathological and physiological hypertrophy may influence therapeutic strategies for the treatment of cardiovascular disease and heart failure. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Philosophical Transactions of the Royal Society B: Biological Sciences
                Phil. Trans. R. Soc. B
                The Royal Society
                0962-8436
                1471-2970
                January 19 2018
                December 04 2017
                January 19 2018
                : 373
                : 1738
                : 20160530
                Affiliations
                [1 ]Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
                [2 ]Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University, Chicago, IL 60302, USA
                [3 ]Department of Pathology and Laboratory Medicine, McAllister Heart Institute, CB#7525, Chapel Hill, NC 27599-7525, USA
                Article
                10.1098/rstb.2016.0530
                5717530
                29203715
                48627f84-09d4-42de-b058-5fc115ffac49
                © 2018

                https://royalsociety.org/journals/ethics-policies/data-sharing-mining/

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