Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death

Author:

Ghosh Rajeshwary12,Gillaspie Jennifer Jason1,Campbell Kenneth S.3ORCID,Symons J. David2,Boudina Sihem2,Pattison James Scott1ORCID

Affiliation:

1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota

2. Department of Nutrition and Integrative Physiology Program in Molecular Medicine, University of Utah, Salt Lake City, Utah

3. Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky

Abstract

Chaperone-mediated autophagy (CMA) is a chaperone-dependent process of selective cytosolic protein turnover that targets specific proteins to lysosomes for degradation. Enhancing protein degradation mechanisms has been shown to be beneficial in multiple models of cardiac disease, including myocardial infarction (MI) and ischemia-reperfusion (I/R) injury. However, the causal role of CMA in cardiomyocyte injury and death is largely unknown. Hypoxia is an important contributor to both MI and I/R damage, which are major, precedent causes of heart failure. Upregulating CMA was hypothesized to protect against hypoxia-induced cardiomyocyte death. Lysosome-associated membrane protein 2a ( Lamp2a) overexpression and knockdown were used to causally study CMA’s role in hypoxically stressed cardiomyocytes. LAMP2a protein levels were used as both a primary indicator and driver of CMA function. Hypoxic stress was stimulated by CoCl2 treatment, which increased LAMP2a protein levels (+1.4-fold) and induced cardiomyocyte apoptosis (+3.2–4.0-fold). Lamp2a siRNA knockdown (−3.2-fold) of control cardiomyocytes increased apoptosis (+1.8-fold) suggesting that loss of CMA is detrimental for cardiomyocyte survival. However, there was neither an additive nor a synergistic effect on cell death when Lamp2a-silenced cells were treated with CoCl2. Conversely, Lamp2a overexpression (+3.0-fold) successfully reduced hypoxia-induced apoptosis by ∼50%. LAMP2a was also significantly increased (+1.7-fold) in ischemic heart failure patient samples, similar to hypoxically stressed cardiomyocytes. The failing ischemic hearts may have had insufficient CMA activation. To our knowledge, this study for the first time establishes a protective role for CMA (via Lamp2a overexpression) against hypoxia-induced cardiomyocyte loss and reveals the intriguing possibility that CMA activation may offer a cardioprotective treatment for ischemic heart disease.

Funder

American Heart Association

HHS | NIH | National Heart, Lung, and Blood Institute

HHS | NIH | National Institute of General Medical Sciences

University of Utah

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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