Cardioprotection with alpha-tocopheryl phosphate: amelioration of myocardial ischemia reperfusion injury is linked with its ability to generate a survival signal through Akt activation.
The emerging potential of alpha-tocopheryl phosphate, a phosphoric acid ester of alpha-tocopherol, in health benefits was tested gavaging this compound (5 mg/kg body wt) to a group of rats for a period of thirty days while the control rats were given water only. After thirty days, the rats were sacrificed, the hearts excised, and the isolated hearts were perfused by working mode. Both control and experimental hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The tocopheryl phosphate fed rats exhibited significant cardioprotection as evidenced by improved ventricular performance and reduced myocardial infarct size and cardiomyocyte apoptosis. Supplementation with alpha-tocopheryl phosphate converted MAP kinase-induced death signal into a survival signal by enhancing anti-apoptotic p42/44 ERK kinase and p38 MAPKbeta and reducing pro-apoptotic proteins p38 MAPKalpha and JNK. In concert, the phosphorylation of pro-apoptotic c-Src was also reduced. Tocopheryl phosphate increased the DNA binding of the redox-sensitive transcription factor NFkappaB and potentiated the activation of anti-death protein Bcl-2 and survival signaling protein Akt. The results of this study demonstrated for the first time that tocopheryl phosphate could ameliorate myocardial ischemic reperfusion injury by converting ischemia/reperfusion-mediated death signal into a survival signal by modulating MAP kinase signaling.
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Subhendu
S
Mukherjee
Istvan
I
Lekli
Manika
M
Das
Angelo
A
Azzi
Dipak K
DK
Das
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000494:pharmacology
D002316:Cardiotonic Agents; D016328:NF-kappa B; C012552:alpha-tocopherol phosphate; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt; D024502:alpha-Tocopherol