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Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection

Departments of ¹Anesthesiology, ²Physiology, and ³Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 18 July 2007 ; accepted in final form 9 January 2008

From time of their discovery, sarcolemmal ATP-sensitive K⁺ (sarcK_ATP) channels were thought to have an important protective role in the heart during stress whereby channel opening protects the heart from stress-induced Ca²⁺ overload and resulting damage. In contrast, some recent studies indicate that sarcK_ATP channel closing can lead to cardiac protection. Also, the role of the sarcK_ATP channel in apoptotic cell death is unclear. In the present study, the effects of channel inhibition on apoptosis and the specific interaction between the sarcK_ATP channel and mitochondria were investigated. Apoptotic cell death of cultured HL-1 and neonatal cardiomyocytes following exposure to oxidative stress was significantly increased in the presence of sarcK_ATP channel inhibitor HMR-1098 as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3,7 assays. This was paralleled by an increased release of cytochrome c from mitochondria to cytosol, suggesting activation of the mitochondrial death pathway. sarcK_ATP channel inhibition during stress had no effect on Bcl-2, Bad, and phospho-Bad, indicating that the increase in apoptosis cannot be attributed to these modulators of the apoptotic pathway. However, monitoring of mitochondrial Ca²⁺ with rhod-2 fluorescent indicator revealed that mitochondrial Ca²⁺ accumulation during stress is potentiated in the presence of HMR-1098. In conclusion, this study provides novel evidence that opening of sarcK_ATP channels, through a specific Ca²⁺-related interaction with mitochondria, plays an important role in preventing cardiomyocyte apoptosis and mitochondrial damage during stress.

cardioprotection; mitochondrial calcium; cardiomyocytes

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