Integrins protect cardiomyocytes from ischemia/reperfusion injury

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. KaufmanHemal H. Patel, David M. Roth, H. Kirk Hammond, Susan S. Taylor, Wolfgang H. Dillmann, Joshua I. Goldhaber, Robert S. Ross

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 Ca 2+ 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 Ca 2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.

Original languageEnglish
Pages (from-to)4294-4308
Number of pages15
JournalJournal of Clinical Investigation
Volume123
Issue number10
DOIs
Publication statusPublished - 2013 Oct 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Okada, H., Lai, N. C., Kawaraguchi, Y., Liao, P., Copps, J., Sugano, Y., Okada-Maeda, S., Banerjee, I., Schilling, J. M., Gingras, A. R., Asfaw, E. K., Suarez, J., Kang, S. M., Perkins, G. A., Au, C. G., Israeli-Rosenberg, S., Manso, A. M., Liu, Z., Milner, D. J., ... Ross, R. S. (2013). Integrins protect cardiomyocytes from ischemia/reperfusion injury. Journal of Clinical Investigation, 123(10), 4294-4308. https://doi.org/10.1172/JCI64216