BKCa Channel Activation Increases Mitochondrial Supercomplexes and Improves Cardiac Recovery in a Large Animal Model of Myocardial Stunning Following Cardioplegic Arrest and Cardiopulmonary Bypass

Cardiac surgery or transplant using cardioplegic arrest and cardiopulmonary bypass (CP/CPB) subjects the heart to mild reversible ischemic injury that results in pronounced myocardial stunning. Mitochondrial large conductance calcium-activated K+ channels (BKCa) in cardiomyocytes are potently cardioprotective and beneficially modulate respiration and ROS post-I/R injury. However, how BKCa-dependent K+ flux regulates ROS and respiration is unclear. We evaluated the BKCa activator rottlerin in a preclinical large animal pig CP/CPB model of myocardial stunning and evaluated BKCa-dependent cardioprotective mechanisms in vitro and in vivo. BKCa activation with the small molecule rottlerin significantly improved LV cardiac functional recovery and contractility at 1 h reperfusion. TEM showed larger mitochondria in the rottlerin group consistent with K+ influx. We also found that pigs with rottlerin treatment had increased electron transport chain supercomplexes (mSCs), which are thought to improve respiratory efficiency and reduce ROS. Consistent with increased mSC, rottlerin reduced ROS-dependent protein modification in CP/CPB pigs. In complementary studies, rottlerin and/or adenoviral overexpression of a mutant mito-BKCa increased respiration, altered mitochondrial morphology, increased mSC assembly, and significantly reduced ROS following in vitro CP/reoxygenation, similar to CP/CPB pigs. In summary, mito-BKCa activation increases mSCs and respiration while reducing ROS, suggesting that mSC-dependent improved respiratory efficiency promotes robust cardioprotection.