The cardioprotective effect of postconditioning is mediated by ARC through inhibiting mitochondrial apoptotic pathway.
OBJECTIVE
Postconditioning protects the heart against ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. However, the molecular mechanism by which postconditioning suppresses apoptosis remains to be fully understood. Apoptosis repressor with caspase recruitment domain (ARC) has been demonstrated to possess the ability to protect cardiomyocytes from apoptosis induced by ischemia/reperfusion. It is not yet clear as to whether ARC contributes to the inhibitory effect of postconditioning against cardiomyocyte apoptosis.


METHODS
The cultured cardiomyocytes from 1-day old male Sprague-Dawley rats were exposed to 3 h hypoxia followed by 3 h of reoxygenation. Cells were postconditioned by three cycles each of 5 min reoxygenation and 5 min hypoxia before 3 h of reoxygenation.


RESULTS
Hypoxia/reoxygenation led to a decrease of endogenous ARC protein levels. In contrast, postconditioning could block the reduction of endogenous ARC protein levels. Interestingly, inhibition of endogenous ARC expression by ARC antisense oligodeoxynucleotides reduced the inhibitory effect of postconditioning against apoptosis. Furthermore, our data showed that postconditioning suppressed the loss of mitochondrial membrane potential, Bax activation and the release of mitochondrial cytochrome c to cytosol. However, these inhibitory effects of postconditioning disappeared upon knockdown of endogenous ARC.


CONCLUSIONS
Our data for the first time demonstrate that ARC plays an essential role in mediating the cardioprotective effect of postconditioning against apoptosis initiated by the mitochondrial pathway.
Li
YuZhen
Y
Department of Pathophysiology, Institute of Basic Medical Science, Chinese PLA General Hospital, 100853 Beijing, China. yuzlif96@yahoo.com.cn
Ge
Xinlan
X
Liu
XiuHua
X
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D003600:Cytosol / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D009124:Muscle Proteins / Q000172:deficiency / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D011487:Protein Conformation; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C491788:Nol3 protein, rat; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c