ARC contributes to the inhibitory effect of preconditioning on cardiomyocyte apoptosis.
Inhibition of cardiomyocyte apoptosis plays a key role in preconditioning-triggered cardioprotection. However, the molecular mechanism(s) by which preconditioning inhibits apoptosis is not fully understood. Apoptosis repressor with caspase recruitment domain (ARC) possesses the ability to block hypoxia-induced cardiomyocyte apoptosis. We tested whether ARC contributes to the inhibitory effect of preconditioning on cardiomyocyte apoptosis. Cardiomyocytes from 1-day-old male Sprague-Dawley rats were preconditioned by exposing to 10 min of hypoxia, followed by 30 min of reoxygenation. Then, the preconditioned and non-preconditioned cardiomyocytes were exposed to 90 min of hypoxia followed by 120 min of reoxygenation. The results showed that preconditioning inhibited cell death induced by hypoxia and reoxygenation. Hypoxia and reoxygenation could induce a decrease of ARC protein levels. Intriguingly, preconditioning could maintain ARC protein levels. Inhibition of endogenous ARC expression by ARC antisense oligonucleotides reduced the inhibitory effect of preconditioning on apoptosis. Furthermore, preconditioning-induced suppression of the release of mitochondrial cytochrome c to cytosol and caspase-3 activation could be abolished by the inhibition of endogenous ARC expression using ARC antisense oligonucleotides.


CONCLUSIONS
These data indicate that ARC participates in preconditioning-triggered cardioprotection by interfering with cytochrome c release and caspase-3 activation.
Li
Yu Zhen
YZ
Department of Pathophysiology, Institute of Basic Medical Science, PLA General Hospital, 100853 Beijing, China.
Liu
Xiu Hua
XH
Zhu
Xiao Mei
XM
Cai
Li Rong
LR
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009124:Muscle Proteins / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C491788:Nol3 protein, rat; D016376:Oligonucleotides, Antisense; D045304:Cytochromes c; D053148:Caspase 3