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

Integrins protect cardiomyocytes from ischemia/reperfusion injury

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 7

Integrins colocalized with RyR2 in T-tubules.

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Integrins colocalized with RyR2 in T-tubules. (A and B) β1D integrin loc...
(A and B) β1D integrin localizes in T-tubules. Integrin (green) with (A) wheat germ agglutinin (WGA, red) and (B) junctophilin-2 (JP-2, red). Scale bar: 20 μm. (C–G) β1D integrin colocalizes with RyR2 in CMs. (C) Immunofluorescent microscopy: β1D integrin (green) and RyR2 (red) colocalized. Scale bar: 20 μm. (D) Confocal 3D analysis shows β1D integrin (green) and RyR2 (red) are tightly colocalized (Pearson coefficient of 0.83 ± 0.09 [n = 10]). Scale bar: 20 μm. (E–G) Immunoelectron microscopy shows colocalization of β1D integrin and RyR2. (E) Immunoelectron microscopy of ARVM T-tubule. Scale bar: 200 nm. The boxed area is shown at higher magnification in F and G. (F) Magnified image of T-tubule and SR. The green arrow indicates RyR2 (6-nm gold particle); the red arrow indicates β1D integrin (10-nm gold particle); and blue arrows indicate colocalized particles in the T-tubule. Scale bar: 100 nm. (G) Diagram of F. Blue arrows indicate colocalization of β1D integrin (red dots) and RyR2 (green dots). Scale bar: 100 nm.