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Integrins protect cardiomyocytes from ischemia/reperfusion injury
Hideshi Okada, … , Joshua I. Goldhaber, Robert S. Ross
Hideshi Okada, … , Joshua I. Goldhaber, Robert S. Ross
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4294-4308. https://doi.org/10.1172/JCI64216.
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Research Article Cardiology Article has an altmetric score of 8

Integrins protect cardiomyocytes from ischemia/reperfusion injury

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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.

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

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Figure 10

The β1D integrin cytoplasmic domain variant is necessary for protection from reoxygenation injury.

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The β1D integrin cytoplasmic domain variant is necessary for protection ...
(A and B) Protection from reoxygenation injury occurs with the β1D but not the β1A integrin splice variant. (A) Survival rate of cells assayed by trypan blue staining after H/R injury. α7β1D integrin OE inhibited cell death compared with that in control cells. In contrast, α5β1D integrin had no beneficial effect against H/R. *P < 0.05 vs. LacZ (1-way ANOVA). (B) Cell survival evaluated by LDH release after H/R confirmed data in A. *P < 0.05 vs. LacZ following reoxygenation (1-way ANOVA). (C) Mitochondrial membrane potential was maintained by α7β1D but not α7β1A integrin following H/R injury. Mitochondrial membrane potential measured with the membrane potential–sensitive dye JC-1 after H/R. The excitation ratio (red/green) indicates the mitochondrial membrane potential. Cells in which α7β1D OE maintained the mitochondrial membrane potential during reoxygenation injury, in comparison with control virus (LacZ) or α7β1A integrin. *P < 0.05 vs. LacZ (1-way ANOVA). (D) Mitochondrial [Ca2+] measured using pericam excitation ratio during reoxygenation. In cells infected with α7β1D, mitochondrial [Ca2+] was maintained in comparison with the LacZ (control) or α7β1A-infected cells in which it increased. *P < 0.05 vs. LacZ (1-way ANOVA). (E and F) α7β1A did not interact with RyR2 in ARVM protein extracts. IPs were performed using IgG as a negative control and (E) anti-β1A integrin or (F) RyR2 antibodies.

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