Activation of mitochondrial K(ATP) channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway.
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 approximately 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.
Takashi
E
E
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0529, USA.
Wang
Y
Y
Ashraf
M
M
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009203:Myocardial Infarction / Q000503:physiopathology*; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D011493:Protein Kinase C