Activation of mitochondrial K(ATP) channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway

En Takashi, Yigang Wang, Muhammad Ashraf

Research output: Contribution to journalArticle

146 Scopus citations

Abstract

Activation of mitochondrial K(ATP) (mitoK(ATP)) channel induces acute ischemic preconditioning (PC) against ischemic injury. The ability of this channel to elicit late PC remains unknown. The present study tests the hypothesis that stimulation of mitoK(ATP) channel induces late PC via the protein kinase C (PKC) signaling pathway. Rats were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion (I/R). In other groups, rats were pretreated with diazoxide, a specific opener of the mitoK(ATP) channel (7 mg/kg, IV), 12, 24, 48, and 72 hours before they were subjected to I/R. A maximum reduction in infarct size was observed after 24 hours (33.3 ± 2.2% versus I/R group, 62.1 ± 2.4%). Pretreatment with diazoxide did not reduce the infarct size significantly after 12, 48, and 72 hours (50.2 ± 4.3%, 50.5 ± 4.6%, and 58.2 ± 4.9%) compared with the I/R group. The protection was blocked with 5-hydroxydecanoic acid (5-HD, 5 mg/kg IV), a relatively selective mitoK(ATP) channel blocker (56.5 ± 2.7%), and chelerythrine (5 mg/kg IV), an effective PKC inhibitor (57.1 ± 3.4%) administered either on the first day before diazoxide pretreatment or 10 minutes before I/R on the second day. Cell necrosis was decreased by ≃50% in the diazoxide preconditioned hearts compared with control I/R hearts. Cell death by apoptosis was also significantly decreased in diazoxide pretreated hearts (3.2%) as compared with I/R (11.3%). In conclusion, activation of mitoK(ATP) channel with diazoxide produces late PC against reperfusion injury. The effect of mitoK(ATP) channel appears to be dependent on the PKC- mediated signal pathway.

Original languageEnglish (US)
Pages (from-to)1146-1153
Number of pages8
JournalCirculation research
Volume85
Issue number12
DOIs
Publication statusPublished - Dec 3 1999
Externally publishedYes

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Keywords

  • Apoptosis
  • Electron microscopy
  • Mitochondrial K(ATP) channel
  • Myocardial infarction
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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