Survivin: a novel player in insulin cardioprotection against myocardial ischemia/reperfusion injury.
Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the activation of a survival signaling cascade including the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. However, the down-stream mechanism of PI3K remains elusive. This study is aimed at investigating whether survivin (SVV) plays a role in the insulin-induced anti-apoptotic effect in the ischemic/reperfused (I/R) hearts, and if so, further determining the signaling mechanism involved. Isolated adult rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin (10(-7)mol/L) at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, along with significantly up-regulated myocardial SVV expression (5.9±0.3 Group MI/R+Ins vs. 2.1±0.1 Group MI/R, p<0.05) and increased phosphorylations of mTOR and p70S6K compared with I/R group, which was blocked by pretreatment of PI3K inhibitor LY294002. Rapamycin, a specific mTOR inhibitor, did not alter insulin-induced Akt phosphorylation but significantly inhibited SVV expression (from 6.1±0.3 to 3.0±0.15, p<0.05). Moreover, rapamycin blunted insulin-induced anti-apoptosis in the I/R hearts (8.1±0.4% vs. 16.5±1.8%, p<0.05). To further ascertain the role of SVV in insulin-induced cardioprotection, cardiomyocytes were transfected with adenovirus encoding SVV (gain-of-function) or siRNA targeting SVV (loss-of-function). Overexpression of SVV decreased I/R-induced cardiomyocyte apoptosis in vitro, while siRNA targeting SVV significantly blunted the anti-apoptotic effect of insulin. Taken together, these results suggest a novel role of PI3K/Akt/mTOR/SVV signaling in the cardioprotective effect of insulin.
Si
Rui
R
Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Tao
Ling
L
Zhang
Hai F
HF
Yu
Qiu J
QJ
Zhang
Rui
R
Lv
An L
AL
Zhou
Ning
N
Cao
Feng
F
Guo
Wen Y
WY
Ren
Jun
J
Wang
Hai C
HC
Gao
Feng
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C516989:Birc5 protein, rat; D007328:Insulin; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; C546845:mTOR protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases