title: 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. The purpose of this study was to test whether NO induces cardioprotection against ischemia/reperfusion by inhibiting oxidative stress through mitochondrial zinc and Src tyrosine kinase. The NO donor S-nitroso-N-acetyl penicillamine (SNAP) given before the onset of ischemia reduced cell death in rat cardiomyocytes subjected to simulated ischemia/reperfusion, and this was abolished by the zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and the Src tyrosine kinase inhibitor PP2. SNAP also prevented loss of mitochondrial membrane potential (ΔΨm) at reperfusion, an effect that was blocked by TPEN and PP2. SNAP increased mitochondrion-free zinc upon reperfusion and enhanced mitochondrial Src phosphorylation in a zinc-dependent manner. SNAP inhibited both mitochondrial complex I activity and mitochondrial reactive oxygen species (ROS) generation at reperfusion through zinc and Src tyrosine kinase. Finally, the anti-infarct 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 the inhibition of complex I at reperfusion. Activation of mitochondrial Src tyrosine kinase by zinc may account for the inhibition of complex I.
authors.affiliation: Heart Institute, Hebei United University, Tanshan, Hebei, P R China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Xing
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: J
authors.initials: J
authors.lastname: Xi
authors.forename: X
authors.initials: X
authors.lastname: Cui
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D019061:src-Family Kinases; D015032:Zinc