| First Author | Okada H | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 10 | Pages | 4294-308 |
| PubMed ID | 24091324 | Mgi Jnum | J:203982 |
| Mgi Id | MGI:5529378 | Doi | 10.1172/JCI64216 |
| Citation | Okada H, et al. (2013) Integrins protect cardiomyocytes from ischemia/reperfusion injury. J Clin Invest 123(10):4294-308 |
| abstractText | 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 alpha7beta1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of beta1 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 alpha7beta1D exposed to I/R had a substantial reduction in infarct size compared with that of alpha5beta1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that alpha7beta1D 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 beta1D 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 alpha7beta1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury. |
