Ischemic preconditioning targets the reperfusion phase
- 161 Downloads
Emerging studies suggest that signaling during the myocardial reperfusion phase contributes to ischemic preconditioning (IPC). Whether the activation of PKC, the opening of the mKATP channel, redox signaling and transient acidosis specifically at the time of myocardial reperfusion are required to mediate IPC-induced protection is not known. Langendorff-perfused rat hearts were subjected to 35 min ischemia followed by 120 min reperfusion at the end of which infarct size was determined by tetrazolium staining. Control and IPC-treated hearts were randomized to receive for the first 15 min of reperfusion: (1) DMSO (0.02%) vehicle control; (2) chelerythrine (10 μmol/l), a PKC antagonist; (3) 5 hydroxydecanoate (5- HD,100 μmol/l), a mKATP channel blocker; (4) N-mercaptopropionylglycine (MPG,1 mmol/l), a reactive oxygen species scavenger; (5) NaHCO3 (pH 7.6), to counteract any acidosis. Interestingly, all four agents given at the time of myocardial reperfusion abolished the infarct reduction elicited by IPC (N > 6/group): (1) DMSO at reperfusion: 49.3 ± 3.6% in control versus 21.0 ± 3.6% with IPC:P < 0.05; (2) chelerythrine at reperfusion: 57.1 ± 2.5% in control versus 60.1 ± 3.3% with IPC:P = NS; (3) 5-HD at reperfusion: 53.4 ± 6.5 % in control versus 42.6 ± 4.4% with IPC:P = NS; (4) MPG at reperfusion: 55.3 ± 4.6% in control versus 43.9 ± 5.2% with IPC:P = NS; (5) NaHCO3 at reperfusion 53.4 ± 2.5% in control versus 59.0 ± 3.3% with IPC:P = NS. In conclusion, we report for the first time that PKC activation, mKATP channel opening, redox signaling and a low pH at the time of myocardial reperfusion are required to mediate the cardioprotection elicited by ischemic preconditioning.
Key wordsischemic preconditioning reperfusion mKATP channel PKC redox signaling
Unable to display preview. Download preview PDF.
- 14.Fujita M,Asanuma H,Hirata A,Wakeno M, Takahama H, Sasaki H, Kim J, Takashima S, Tsukamoto O, Minamino T, Shinozaki Y, Tomoike H, Hori M, Kitakaze M (2007) Prolonged Transient Acidosis During Early Reperfusion Contributes to the Cardioprotective Effects of Postconditioning. Am J Physiol Heart Circ Physiol 292:H2004–H2008PubMedCrossRefGoogle Scholar
- 17.Hausenloy DJ,Yellon DM (2007) Reperfusion Injury Salvage Kinase Signaling: Taking a RISK for Cardioprotection. Heart Failure Reviews (in press)Google Scholar
- 18.Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: United at reperfusion.Pharmacol Therapeutics (in press)Google Scholar
- 30.Juhaszova M,Zorov DB,Kim SH,Pepe S, Fu Q, Fishbein KW, Ziman BD,Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase- 3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113:1535–1549PubMedCrossRefGoogle Scholar
- 33.Lecour S, Suleman N, Deuchar GA, Somers S, Lacerda L,Huisamen B, Opie LH (2005) Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signalregulated kinase). Circulation 112:3911–3918PubMedCrossRefGoogle Scholar
- 40.Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G,Pagliaro P (2006) Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATPsensitive K+ channel and protein kinase C activation. Basic Res Cardiol 101:180–189PubMedCrossRefGoogle Scholar