Year: 2013
Type: article
Abstract: Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7β1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of β1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7β1D exposed to I/R had a substantial reduction in infarct size compared with that of α5β1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7β1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that β1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7β1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.
DOI: 10.1172/jci64216
Authors: Hideshi Okada, N. Chin Lai, Yoshitaka Kawaraguchi, Peter Liao, Jeffrey Copps, Yasuo Sugano, Sunaho Okada-Maeda, Indroneal Banerjee, Jan M. Schilling, Alexandre R. Gingras, Elizabeth K. Asfaw, Jorge Suarez, Seok-Min Kang, Guy A. Perkins, Carol G. Au, Sharon Israeli-Rosenberg, Ana Maria Manso, Zheng Liu, Derek J. Milner, Stephen J. Kaufman, Hemal H. Patel, David M. Roth, H. Kirk Hammond, Susan S. Taylor, Wolfgang H. Dillmann, Joshua I. Goldhaber, Robert S. Ross
Institutions: United States Department of Veterans Affairs, University of California San Diego, VA San Diego Healthcare System, Howard Hughes Medical Institute, New York State Department of Health, Wadsworth Center, University of Illinois Urbana-Champaign, Cedars-Sinai Medical Center, Cedars-Sinai Smidt Heart Institute
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Howard Hughes Medical Institute, Eli Lilly and Company, Muscular Dystrophy Association, University of Pennsylvania, Loyola University Chicago, Cedars-Sinai Medical Center, Kanae Foundation for the Promotion of Medical Science, National Institutes of Health, Loyola University Chicago Stritch School of Medicine, University of California, San Diego, National Institute on Aging, National Heart, Lung, and Blood Institute
Awards: Calcium Signaling, Metabolism, and EC Coupling in Heart, G2158449602, Role of the Alpha 7 Beta 1 Integrin in Muscle Integrity, Molecular Pathways for Hypertrophy and Cardiomyopathy, G5520316217, Structural Basis of Dysfunctional Calcium Release Channels in Heart Disease, Integrin Function in Cardiac Remodeling, G829105684, Cardiomyocyte mechanotransduction through the integrin complex, G9000343213, Training in Cardiovascular Physiology and Pharmacology
OpenAlex ID: W1977731744