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Am J Physiol Heart Circ Physiol 281: H1295-H1303, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 3, H1295-H1303, September 2001

Mitochondrial KATP channel activation reduces anoxic injury by restoring mitochondrial membrane potential

Meifeng Xu, Yigang Wang, Ahmar Ayub, and Muhammad Ashraf

Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529

Mitochondrial membrane potential (Delta Psi m) is severely compromised in the myocardium after ischemia-reperfusion and triggers apoptotic events leading to cell demise. This study tests the hypothesis that mitochondrial ATP-sensitive K+ (mitoKATP) channel activation prevents the collapse of Delta Psi m in myocytes during anoxia-reoxygenation (A-R) and is responsible for cell protection via inhibition of apoptosis. After 3-h anoxia and 2-h reoxygenation, the cultured myocytes underwent extensive damage, as evidenced by decreased cell viability, compromised membrane permeability, increased apoptosis, and decreased ATP concentration. Mitochondria in A-R myocytes were swollen and fuzzy as shown after staining with Mito Tracker Orange CMTMRos and in an electron microscope and exhibited a collapsed Delta Psi m, as monitored by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Cytochrome c was released from mitochondria into the cytosol as demonstrated by cytochrome c immunostaining. Activation of mitoKATP channel with diazoxide (100 µmol/l) resulted in a significant protection against mitochondrial damage, ATP depletion, cytochrome c loss, and stabilized Delta Psi m. This protection was blocked by 5-hydroxydecanoate (500 µmol/l), a mitoKATP channel-selective inhibitor, but not by HMR-1098 (30 µmol/l), a putative sarcolemmal KATP channel-selective inhibitor. Dissipation of Delta Psi m also leads to opening of mitochondrial permeability transition pore, which was prevented by cyclosporin A. The data support the hypothesis that A-R disrupts Delta Psi m and induces apoptosis, which are prevented by the activation of the mitoKATP channel. This further emphasizes the therapeutic significance of mitoKATP channel agonists in the prevention of ischemia-reperfusion cell injury.

apoptosis; myocytes; ATP; permeability transition pore; cytochrome c


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