Integrins protect cardiomyocytes from ischemia/reperfusion injury

Okada, Hideshi, Lai, N.Chin, Kawaraguchi, Yoshitaka, Liao, Peter, Copps, Jeffrey, Sugano, Yasuo, Okada-Maeda, Sunaho, Banerjee, Indroneal, Schilling, Jan M., Gingras, Alexandre R., Asfaw, Elizabeth K., Suarez, Jorge, Kang Jorge, Perkins, Guy A., Au, Carol G., Israeli-Rosenberg, Sharon, Manso, Ana Maria, Liu, Zheng, Milner, Derek J., Kaufman, Stephen J., Patel, Hemal H., Roth, David M., Hammond, H. Kirk, Taylor, Susan S., Dillmann, Wolfgang H., Goldhaber, Joshua I. and Ross, Robert S. (2013) Integrins protect cardiomyocytes from ischemia/reperfusion injury. Journal of Clinical Investigation, 123 10: 4294-4308. doi:10.1172/JCI64216

Author Okada, Hideshi
Lai, N.Chin
Kawaraguchi, Yoshitaka
Liao, Peter
Copps, Jeffrey
Sugano, Yasuo
Okada-Maeda, Sunaho
Banerjee, Indroneal
Schilling, Jan M.
Gingras, Alexandre R.
Asfaw, Elizabeth K.
Suarez, Jorge
Kang Jorge
Perkins, Guy A.
Au, Carol G.
Israeli-Rosenberg, Sharon
Manso, Ana Maria
Liu, Zheng
Milner, Derek J.
Kaufman, Stephen J.
Patel, Hemal H.
Roth, David M.
Hammond, H. Kirk
Taylor, Susan S.
Dillmann, Wolfgang H.
Goldhaber, Joshua I.
Ross, Robert S.
Title Integrins protect cardiomyocytes from ischemia/reperfusion injury
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
Publication date 2013-10-01
Year available 2013
Sub-type Article (original research)
DOI 10.1172/JCI64216
Open Access Status DOI
Volume 123
Issue 10
Start page 4294
End page 4308
Total pages 15
Place of publication Ann Arbor, United States
Publisher American Society for Clinical Investigation
Language eng
Formatted 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.
Keyword Immunology
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 AI23847
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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