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 ?7?1D 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 ?7?1D exposed to I/R had a substantial reduction in infarct size compared with that of ?5?1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that ?7?1D 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 ?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 ?7?1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.

SUBMITTER: Okada H 

PROVIDER: S-EPMC3784521 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature