© 1999 American Heart Association, Inc.
Integrative Physiology |
Activation of Mitochondrial ATP-Sensitive K+ Channel for Cardiac Protection Against Ischemic Injury Is Dependent on Protein Kinase C Activity
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. E-mail muhammad.ashraf{at}uc.edu
Abstract—Protein kinase C (PKC)
is involved in the second messenger signaling cascade during
ischemic and Ca2+ preconditioning. Given that the
pharmacological activation of mitochondrial ATP-sensitive
K+ (mitoKATP) channels also mimics
preconditioning, the mechanisms linking PKC activation and
mitoKATP channels remain to be established. We hypothesize
that PKC activity is important for the opening of the
mitoKATP channel. To examine this, a specific opener of the
mitoKATP channel, diazoxide, was used in conjunction with
subcellular distribution of PKC in a model of
ischemia/reperfusion (I/R). Langendorff-perfused rat hearts
were subjected to 40-minute ischemia followed by 30-minute
reperfusion. Effects of activation of the mitoKATP channel
and other interventions on functional, biochemical, and pathological
changes in ischemic hearts were assessed. In hearts treated
with diazoxide, left ventricular end-diastolic
pressure and coronary flow were significantly improved after
I/R; lactate dehydrogenase release was also significantly decreased.
The morphology was well preserved in diazoxide-treated hearts compared
with nontreated ischemic control hearts. The salutary effects
of diazoxide on the ischemic injury were similar to those of
Ca2+ preconditioning. Administration of sodium
5-hydroxydecanoate, an effective blocker of the mitoKATP
channel, or chelerythrine or calphostin C, an inhibitor of
PKC, during diazoxide pretreatment or during continuous presence of
diazoxide in the ischemic period, completely abolished the
beneficial effects of the diazoxide on the I/R injury. Blockade of
Ca2+ entry during diazoxide treatment by inhibiting the
L-type Ca2+ channel with verapamil also
completely reversed the beneficial effect of diazoxide during I/R.
PKC-
was translocated to sarcolemma, whereas PKC-
was
translocated to the mitochondria and intercalated disc, and PKC-
was
translocated to the intercalated disc of the diazoxide-pretreated
hearts. Colocalization studies for mitochondrial distribution with
tetramethylrhodamine ethyl ester (TMRE) and PKC isoforms by
immunoconfocal microscopy revealed that PKC- antibody specifically
stained the mitochondria. ATP was significantly increased in the
diazoxide-treated hearts. Moreover, the data suggest that activation
and translocation of PKC to mitochondria appear to be important for the
protection mediated by mitoKATP channel.
Key Words: mitochondrial KATP channel • preconditioning • ischemia • protein kinase C • ATP
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