The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial KATP channels

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Abstract
The cardioprotective effects of ischemic preconditioning (IPC) can be mimicked or blocked by pharmacologic agents, which modulate the mitochondrial ATP-sensitive potassium (mKATP) channel, thereby implicating this channel in the mechanism of IPC. Cardioprotection can also be achieved via inhibition of mitochondrial respiratory complex II, and significant pharmacologic overlap exists between complex II inhibitors and mKATP channel agonists. However, the relationship between complex II and the mKATP channel remains unclear. Atpenin A5 (AA5) is a potent and specific complex II inhibitor, and herein we report that AA5 (1 nM) also activates the mKATP channel and protects against simulated ischemia-reperfusion (IR) injury in isolated cardiomyocytes. Similar to known mKATP agonists, AA5-mediated protection was sensitive to the mKATP antagonists 5-hydroxydecanoate (5HD) and glyburide. Notably, the optimal mKATP opening and protective concentration of AA5 had no effect on complex II enzymatic activity, suggesting an interaction of AA5 with complex II, but not inhibition of the complex per se, is necessary for protection. A cardioprotective effect of AA5 was also observed in isolated perfused hearts, wherein AA5 increased post-IR contractile function and decreased infarct size, in a 5HD-sensitive manner. In conclusion, the specific complex II inhibitor AA5 is the most potent mKATP activator discovered to date, and provides a novel method of activating mKATP channels and protecting the heart from IR injury.

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