Cytoprotective effect of bis(1-oxy-2-pyridinethiolato)oxovanadiun(IV) on myocardial ischemia/reperfusion injury elicits inhibition of Fas ligand and Bim expression and elevation of FLIP expression.
VO(OPT), bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), has been shown to increase tyrosine phosphorylation of proteins and promote the insulin receptor signaling, thereby elicit anti-diabetic action. We here investigated the cytoprotective action of VO(OPT) on myocardial infarction and cardiac functional recovery in rats subjected to myocardial ischemia/reperfusion and defined mechanisms underlying its cytoprotective action. Rats underwent 30 min myocardial ischemia by left anterior descending coronary artery occlusion followed by 24 h reperfusion. Post-ischemic treatment with VO(OPT) significantly reduced infarct size and improved cardiac function (left ventricular developed pressure and +/-dP/dt) after 72 h reperfusion and in a dose-dependent manner. Moreover, VO(OPT) treatment also dose-dependently significantly inhibited caspases-3, -9 and -7 processing, thereby elicited the anti-apoptotic effect. The cytoprotective effect of VO(OPT) was closely associated with restoration of Akt activity. The recovered Akt activity correlated with increased phosphorylation of Bad and forkhead transcription proteins, thereby inhibiting apoptotic signaling. Furthermore, treatment with VO(OPT) significantly increased FLIP expression, and decreased expression of Fas ligand and Bim in cardiomyocytes. Taken together, cardiomyocytes rescue following post-treatment with VO(OPT) from ischemia/reperfusion injury was mediated by increased FLIP expression and decreased Fas ligand and Bim expression via activation of Akt. These results demonstrate that treatment with VO(OPT) exerts significant cytoprotective effects along with improvement of cardiac functional recovery.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Md Shenuarin
MS
Bhuiyan
Masatoshi
M
Shibuya
Norifumi
N
Shioda
Shigeki
S
Moriguchi
Jiro
J
Kasahara
Yosiharu
Y
Iwabuchi
Kohji
K
Fukunaga
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001794:Blood Pressure / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003331:Coronary Vessels / Q000601:surgery; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008026:Ligation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494821:Bad protein, rat; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002316:Cardiotonic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009942:Organometallic Compounds; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; C438939:bis(1-oxy-2-pyridinethiolato)oxovanadium(IV); D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases