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 71D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of 1 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 71D exposed to I/R had a substantial reduction in infarct size compared with that of 51D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that 71D 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 Ca 2+ handling proteins in the CM and found that 1D 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 71D integrin modifies Ca 2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.