title: In vivo cardioprotection by S-nitroso-2-mercaptopropionyl glycine.
abstract: The reversible S-nitrosation and inhibition of mitochondrial complex I is a potential mechanism of cardioprotection, recruited by ischemic preconditioning (IPC), S-nitrosothiols, and nitrite. Previously, to exploit this mechanism, the mitochondrial S-nitrosating agent S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) was developed, and protected perfused hearts and isolated cardiomyocytes against ischemia-reperfusion (IR) injury. In the present study, the murine left anterior descending coronary artery (LAD) occlusion model of IR injury was employed, to determine the protective efficacy of SNO-MPG in vivo. Intraperitoneal administration of 1 mg/kg SNO-MPG, 30 min prior to occlusion, significantly reduced myocardial infarction and improved EKG parameters, following 30 min occlusion plus 2 or 24 h reperfusion. SNO-MPG protected to the same degree as IPC, and notably was also protective when administered at reperfusion. Cardioprotection was accompanied by increased mitochondrial protein S-nitrosothiol content, and inhibition of complex I, both of which were reversed after 2 h reperfusion. Finally, hearts from mice harboring a heterozygous mutation in the complex I NDUSF4 subunit were refractory to protection by either SNO-MPG or IPC, suggesting that a fully functional complex I, capable of reversible inhibition is critical for cardioprotection. Overall, these results are consistent with a role for mitochondrial S-nitrosation and complex I inhibition in the cardioprotective mechanism of IPC and SNO-MPG in vivo.
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14620, USA.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Burwell
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ingraham
authors.forename: Cody M
authors.initials: CM
authors.lastname: Spencer
authors.forename: Alan E
authors.initials: AE
authors.lastname: Friedman
authors.forename: Carl A
authors.initials: CA
authors.lastname: Pinkert
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes