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题名:Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemiaCreperfusion injury
作者:Sergiy M. Nadtochiy, Lindsay S. Burwell and Paul S. Brookes
来源:Journal of Molecular and Cellular Cardiology[IF=3.872], Volume 42, Issue 4, April 2007, Pages 812-825
URL :http://dx.doi.org/10.1016/j.yjmcc.2007.01.010
日期:070415
摘要: Sergiy M. Nadtochiya, 1, Lindsay S. Burwellb, 1 and Paul S. Brookesa, ,

aDepartment of Anesthesiology, PO Box 604, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
bDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14620, USA

Received 9 August 2006; revised 8 January 2007; accepted 23 January 2007. Available online 31 January 2007.

Summary

Mitochondrial dysfunction is a key pathologic event in cardiac ischemiaCreperfusion (IR) injury, and protection of mitochondrial function is a potential mechanism underlying ischemic preconditioning (IPC). Acknowledging the role of nitric oxide (NO) in IPC, it was hypothesized that mitochondrial protein S-nitrosation may be a cardioprotective mechanism. The reagent S-nitroso-2-mercaptopropionyl-glycine (SNO-MPG) was therefore developed to enhance mitochondrial S-nitrosation and elicit cardioprotection. Within cardiomyocytes, mitochondrial proteins were effectively S-nitrosated by SNO-MPG. Consistent with the recent discovery of mitochondrial complex I as an S-nitrosation target, SNO-MPG inhibited complex I activity and cardiomyocyte respiration. The latter effect was insensitive to the NO scavenger c-PTIO, indicating no role for NO-mediated complex IV inhibition. A cardioprotective role for reversible complex I inhibition has been proposed, and consistent with this SNO-MPG protected cardiomyocytes from simulated IR injury. Further supporting a cardioprotective role for endogenous mitochondrial S-nitrosothiols, patterns of protein S-nitrosation were similar in mitochondria isolated from Langendorff perfused hearts subjected to IPC, and mitochondria or cells treated with SNO-MPG. The functional recovery of perfused hearts from IR injury was also improved under conditions which stabilized endogenous S-nitrosothiols (i.e. dark), or by pre-ischemic administration of SNO-MPG. Mitochondria isolated from SNO-MPG-treated hearts at the end of ischemia exhibited improved Ca2+ handling and lower ROS generation. Overall these data suggest that mitochondrial S-nitrosation and complex I inhibition constitute a protective signaling pathway that is amenable to pharmacologic augmentation. 2.

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