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Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial KATP channels during reperfusion

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Abstract

This study tested the hypothesis that inhibition of myocardial injury and modulation of mitochondrial dysfunction by postconditioning (Postcon) after 24 h of reperfusion is associated with activation of KATP channels. Thirty dogs undergoing 60 min of ischemia and 24 h of reperfusion (R) were randomly divided into four groups: Control: no intervention at R; Postcon: three cycles of 30 s R alternating with 30 s re-occlusion were applied at R; 5-hydroxydecanoate (5-HD): the mitochondrial KATP channel blocker was infused 5 min before Postcon; HMR1098: the sarcolemmal KATP channel blocker was administered 5 min before Postcon. After 24 h of R, infarct size was smaller in Postcon relative to Control (27 ± 4%* Vs. 39 ± 2% of area at risk), consistent with a reduction in CK activity (66 ± 7* Vs. 105 ± 7 IU/g). The infarct-sparing effect of Postcon was blocked by 5-HD (48 ± 5%†), but was not altered by HMR1098 (29 ± 3%*), consistent with the change in CK activity (102 ± 8† in 5-HD and 71 ± 6* IU/g in HMR1098). In H9c2 cells exposed to 8 h hypoxia and 3 h of reoxygenation, Postcon up-regulated expression of mito-KATP channel Kir6.1 protein, maintained mitochondrial membrane potential and inhibited mitochondrial permeability transition pore (mPTP) opening evidenced by preserved fluorescent TMRE and calcein staining. The protective effects were blocked by 5-HD, but not by HMR1098. These data suggest that in a clinically relevant model of ischemia-reperfusion (1) Postcon reduces infarct size and decreases CK activity after prolonged reperfusion; (2) protection by Postcon is achieved by opening mitochondrial KATP channels and inhibiting mPTP opening. *P < 0.05 Vs. Control; † P < 0.05 Vs. Postcon.

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Acknowledgments

The authors are grateful to Sara Katzmark and Susan Schmarkey for their technical contributions to this study. The authors would also like to thank Dr. Garrett J. Gross and Dr. Keith Garlid for constructive comments in the design of the study. The authors thank Aventis Pharmaceuticals, Frankfurt, Germany for providing HMR1098 for this study. This work was supported by grants from the National Institute of Health to Z-Q Zhao (HL64886) and to J. Vinten-Johansen (HL69487) as well as by funds from the Carlyle Fraser Foundation of Emory Crawford Long Hospital.

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Authors and Affiliations

  1. Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory Crawford Long Hospital, Emory University, 550 Peachtree Street NE, Atlanta, GA, 30308-2225, USA

    James Mykytenko, James G. Reeves, Hajime Kin, Ning-Ping Wang, Amanda J. Zatta, Rong Jiang, Robert A. Guyton, Jakob Vinten-Johansen & Zhi-Qing Zhao

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  1. James Mykytenko
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  2. James G. Reeves
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  3. Hajime Kin
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  9. Zhi-Qing Zhao
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Correspondence to Zhi-Qing Zhao.

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Returned for 1. Revision: 18 October 2007 1. Revision received: 25 February 2008

Returned for 2. Revision: 10 March 2008 2. Revision received: 18 April 2008

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Mykytenko, J., Reeves, J.G., Kin, H. et al. Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial KATP channels during reperfusion. Basic Res Cardiol 103, 472–484 (2008). https://doi.org/10.1007/s00395-008-0731-2

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