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Cardioprotection initiated by reactive oxygen species is dependent on activation of PKC

¹Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London; and ²Department of Urology, University College London, London, United Kingdom

Submitted 27 July 2005 ; accepted in final form 11 April 2006

To examine whether cardioprotection initiated by reactive oxygen species (ROS) is dependent on protein kinase C (PKC), isolated buffer-perfused mouse hearts were randomized to four groups: 1) antimycin A (AA) (0.1 µg/ml) for 3 min followed by 10 min washout and then 30 min global ischemia (I) and 2 h reperfusion (R); 2) controls of I/R alone; 3) AA bracketed with 13 min of N-2-mercaptopropionyl- glycine (MPG) followed by I/R; and 4) MPG (200 µM) alone, followed by I/R. Isolated adult rat ventricular myocytes (ARVM) were exposed to AA (0.1 µg/ml), and lucigenin was used to measure ROS production. Murine hearts and ARVM were exposed to AA (0.1 µg/ml) with or without MPG, and PKC translocation was measured by cell fractionation and subsequent Western blot analysis. Finally, the dependence of AA protection on PKC was determined by the use of knockout mice (–/–) lacking PKC. AA exposure caused ROS production, which was abolished by the mitochondrial uncoupler mesoxalonitrile 4-trifluoromethoxyphenylhydrazone. In addition, AA significantly reduced the percent infarction-left ventricular volume compared with control I/R (26 ± 4 vs. 43 ± 2%; P < 0.05). Bracketing AA with MPG caused a loss of protection (52 ± 7 vs. 26 ± 4%; P < 0.05). AA caused PKC translocation only in the absence of MPG, and protection was lost on the pkc^–/– background (38 ± 3 vs. 15 ± 4%; P < 0.001). AA causes ROS production, on which protection and PKC translocation depend. In addition, protection is absent in PKC null hearts. Our results imply that, in common with ischemic preconditioning, PKC is crucial to ROS-mediated protection.

protein kinase C; ischemic preconditioning

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