Faculty Collaboration Database

Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection. Am J Physiol Heart Circ Physiol 2008 Mar;294(3):H1317-25

Date

01/15/2008

Pubmed ID

18192220

DOI

10.1152/ajpheart.00840.2007

Scopus ID

2-s2.0-41549111466 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

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.

Author List

Marinovic J, Ljubkovic M, Stadnicka A, Bosnjak ZJ, Bienengraeber M

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Apoptosis
Benzamides
Calcium
Cell Line
Cells, Cultured
Cytochromes c
Electrophysiology
KATP Channels
Mice
Microscopy, Confocal
Mitochondria
Myocytes, Cardiac
Oxidative Stress
Potassium Channel Blockers
Proto-Oncogene Proteins c-bcl-2
Rats
Rats, Sprague-Dawley
Sarcolemma
Signal Transduction
bcl-Associated Death Protein