Survivin mediates the anti-apoptotic effect of delta-opioid receptor stimulation in cardiomyocytes.
Survivin is known to be essential for cell division and to inhibit apoptosis during embryonic development and in adult cancerous tissues. However, the cardiovascular role of survivin is unknown. We observed that in cardiomyocytes cultured under conditions of serum and glucose deprivation (DEPV), the levels of survivin, Bcl-2 and extracellular signal-regulated kinase (ERK) were positively correlated with the anti-apoptotic action of a delta-opioid receptor agonist, [D-Ala2, D-Leu5]-enkephalin acetate (DADLE). By contrast, Bax translocation, mitochondrial membrane damage and reactive oxygen species (ROS) production were inversely correlated with the changes of survivin and Bcl-2. The use of RNA interference (RNAi) targeting survivin increased DEPV-induced cardiomyocyte apoptosis, whereas the anti-apoptotic effect of DADLE was blunted by survivin RNAi. Moreover, survivin transfection and overexpression provided protection against DEPV-induced cardiomyocyte apoptosis. Inhibition of ERK prevented the DADLE-induced decrease in apoptosis and Bax translocation, and increase in survivin and Bcl-2. DADLE-induced increase in survivin was also blunted by phosphoinositol 3-kinase (PI 3-kinase) inhibition. In conclusion, the present study provides the first direct evidence of an anti-apoptotic role of survivin mediating the anti-apoptotic effect of delta-opioid receptor activation in cardiomyocytes. ERK and PI 3-kinase were found to be upstream regulators of survivin. Mitochondrial membranes as well as ROS, Bcl-2 and Bax were also involved in this anti-apoptotic action.
Yao
Ling-Ling
LL
Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, 138 Yi Xue Yuan Road, Shanghai 200032, China.
Wang
Yong-Gang
YG
Cai
Wen-Jie
WJ
Yao
Tai
T
Zhu
Yi-Chun
YC
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000502:physiology*; D000077022:Survivin; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C516989:Birc5 protein, rat; D016895:Culture Media, Serum-Free; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D017465:Receptors, Opioid, delta; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose