Co-ordinated autophagy with resveratrol and γ-tocotrienol confers synergetic cardioprotection.
This study compared two dietary phytochemicals, grape-derived resveratrol and palm oil-derived γ-tocotrienol, either alone or in combination, on the contribution of autophagy in cardioprotection during ischaemia and reperfusion. Sprague-Dawley rats weighing between 250 and 300 g were randomly assigned to one of the following groups: vehicle, ischaemia/reperfusion (I/R), resveratrol + I/R, γ-tocotrienol + I/R, resveratrol +γ-tocotrienol + I/R. For resveratrol treatments, the rats were gavaged with resveratrol (2.5 mg/kg) for 15 days while for γ-tocotrienol experiments the rats were gavaged with γ-tocotrienol (0.3 mg/kg) for 30 days. For the combined resveratrol +γ-tocotrienol experiments, the rats were gavaged with γ-tocotrienol for 15 days, and then gavaging continued with resveratrol along with γ-tocotrienol for a further period of 15 days. After 30 days, isolated perfused hearts were subjected to 30 min. of global ischaemia followed by 2 hrs of reperfusion. Our results showed for the first time that at least in part, the cardioprotection (evidenced from the ventricular performance, myocardial infarct size and cardiomyocyte apoptosis) with resveratrol and γ-toctrienol was achieved by their abilities to induce autophagy. Most importantly, resveratrol and γ-tocotrienol acted synergistically providing greater degree of cardioprotection simultaneously generating greater amount of survival signal through the activation of Akt-Bcl-2 survival pathway. Autophagy was accompanied by the activation of Beclin and LC3-II as well as mTOR signalling, which were inhibited by either 3-methyl adenine (3-MA) or Wortmannin. The autophagy was confirmed from the results of transmission electron microscopy and light microscopy as well as with confocal microscopy. It is tempting to speculate that during ischaemia and reperfusion autophagy along with enhanced survival signals helps to recover the cells from injury.
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Istvan
I
Lekli
Diptarka
D
Ray
Subhendu
S
Mukherjee
Narasimman
N
Gurusamy
Md Kaimul
MK
Ahsan
Bela
B
Juhasz
Istvan
I
Bak
Arpad
A
Tosaki
Mihaela
M
Gherghiceanu
Lawrence M
LM
Popescu
Dipak K
DK
Das
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D002316:Cardiotonic Agents; D002839:Chromans; D013267:Stilbenes; D014810:Vitamin E; C013649:plastochromanol 8; D000077185:Resveratrol