© 1999 American Heart Association, Inc.
Integrative Physiology |
Activation of Mitochondrial KATP Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway
From the Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0529.
Abstract—Activation of
mitochondrial KATP (mitoKATP) 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
mitoKATP 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
mitoKATP 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
mitoKATP 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 mitoKATP channel
with diazoxide produces late PC against reperfusion injury. The effect
of mitoKATP channel appears to be dependent on the
PKC-mediated signal pathway.
Key Words: mitochondrial KATP channel • myocardial infarction • apoptosis • protein kinase C • electron microscopy
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