4.7 Article

Hypoxia-induced preconditioning in adult stimulated cardiomyocytes is mediated by the opening and trafficking of sarcolemmal KATP channels

Journal

FASEB JOURNAL
Volume 18, Issue 6, Pages 1046-+

Publisher

FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.04-1602fje

Keywords

ischemia; heart; Kir6.2; SUR2A; cardioprotection

Funding

  1. Biotechnology and Biological Sciences Research Council [S18744, C15048] Funding Source: Medline
  2. British Heart Foundation [PG/02/091/14227] Funding Source: Medline
  3. Wellcome Trust [059528/Z/99/Z/JMW/CP/JF] Funding Source: Medline
  4. Biotechnology and Biological Sciences Research Council [S18744] Funding Source: researchfish

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The opening of sarcolemmal and mitochondrial ATP-sensitive K(+) (K(ATP)) channels in the heart is believed to mediate ischemic preconditioning, a phenomenon whereby brief periods of ischemia/reperfusion protect the heart against myocardial infarction. Here, we have applied digital epifluorescent microscopy, immunoprecipitation and Western blotting, perforated patch clamp electrophysiology, and immunofluorescence/laser confocal microscopy to examine the involvement of K(ATP) channels in cardioprotection afforded by preconditioning. We have shown that adult, stimulated-to-beat, guinea-pig cardiomyocytes survived in sustained hypoxia for similar to17 min. An episode of 5-min-long hypoxia/5-min-long reoxygenation before sustained hypoxia dramatically increased the duration of cellular survival. Experiments with different antagonists of K(ATP) channels, applied at different times during the experimental protocol, suggested that the opening of sarcolemmal K(ATP) channels at the beginning of sustained hypoxia mediate preconditioning. This conclusion was supported by perforated patch clamp experiments that revealed activation of sarcolemmal K(ATP) channels by preconditioning. Immunoprecipitation and Western blotting as well as immunofluorescence and laser confocal microscopy showed that the preconditioning is associated with the increase in K(ATP) channel proteins in sarcolemma. Inhibition of trafficking of K(ATP) channel subunits prevented preconditioning without affecting sensitivity of cardiomyocytes to hypoxia in the absence of preconditioning. We conclude that the preconditioning is mediated by the activation and trafficking of sarcolemmal K(ATP) channels.

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