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

• Published in: American Journal of Physiology: Cell Physiology 2008-03, Vol.294 (3), p.H1317-H1325
• Main Authors: Marinovic, Jasna, Ljubkovic, Marko, Stadnicka, Anna, Bosnjak, Zeljko J, Bienengraeber, Martin
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563

From time of their discovery, sarcolemmal ATP-sensitive K super(+) (sarcK sub(ATP)) channels were thought to have an important protective role in the heart during stress whereby channel opening protects the heart from stress-induced Ca super(2+) overload and resulting damage. In contrast, some recent studies indicate that sarcK sub(ATP) channel closing can lead to cardiac protection. Also, the role of the sarcK sub(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 sub(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 sub(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 sub(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 Ca super(2+) with rhod-2 fluorescent indicator revealed that mitochondrial Ca super(2+) accumulation during stress is potentiated in the presence of HMR-1098. In conclusion, this study provides novel evidence that opening of sarcK sub(ATP) channels, through a specific Ca super(2+)-related interaction with mitochondria, plays an important role in preventing cardiomyocyte apoptosis and mitochondrial damage during stress.