The roles of mitochondrial Src tyrosine kinase and zinc in nitric oxide‐induced cardioprotection against ischemia/reperfusion injury

Abstract

While nitric oxide (NO) induces cardioprotection by targeting the mitochondrial permeability transition pore (mPTP), the precise mitochondrial signaling events that mediate the action of NO remain unclear. This study tested if NO induces cardioprotection against ischemia/reperfusion by inhibiting oxidative stress through mitochondrial zinc and Src tyrosine kinase. The NO donor SNAP reduced cell death in rat cardiomyocytes subjected to ischemia/reperfusion and this was abolished by the zinc chelator TPEN and the Src tyrosine kinase inhibitor PP2. SANP also prevented loss of mitochondrial membrane potential (¦¤¦·m) at reperfusion, an effect that was blocked by TPEN and PP2. SNAP increased mitochondrial zinc and enhanced mitochondrial Src phosphorylation in a zinc‐dependent manner. SNAP inhibited both mitochondrial complex I activity and ROS generation at reperfusion through zinc and Src tyrosine kinase. Finally, the antiinfarct effect of SNAP was abrogated by TPEN and PP2 applied at reperfusion in isolated rat hearts. In conclusion, NO induces cardioprotection at reperfusion by targeting mitochondria through attenuation of oxidative stress resulted from inhibition of complex I at reperfusion. Activation of mitochondrial Src tyrosine kinase by zinc may account for inhibition of complex I.