Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes.
Tocotrienols, isomers of vitamin E, have been found to possess many health benefits. The present study was designed to determine whether tocotrienol has a direct cardioprotective role. Isolated rat hearts were perfused for 15 min with Krebs-Ringer bicarbonate buffer in the absence or presence of palm tocotrienol derived from the tocotrienol-rich fraction (0.035%) of palm oil (TRF). In another group of studies, the hearts were preperfused for 15 min in the presence of a c-Src inhibitor, 4-amino-5-(4-methylphenyl)-7-(t-butyl)-pyrazolo-3,4-d-pyrimidine (PPI). The hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. As expected, ischemia-reperfusion caused ventricular dysfunction, electrical rhythm disturbances, and increased myocardial infarct size. PPI or TRF could reverse the ischemia-reperfusion-mediated cardiac dysfunction. Ischemia-reperfusion also upregulated c-Src expression and phosphorylation. Although TRF only minimally affected c-Src expression, it significantly inhibited the phosphorylation of c-Src. Ischemia-reperfusion reduced 20S and 26S proteasome activities, an effect prevented by TRF pretreatment. PPI exerted a cardioprotective effect that is not mediated by the proteasome but, rather, through direct inhibition of c-Src. The results of this study support a role for c-Src in postischemic cardiac injury and dysfunction and demonstrate direct cardioprotective effects of TRF. The cardioprotective properties of TRF appear to be due to inhibition of c-Src activation and proteasome stabilization.
Das
Samarjit
S
Cardiovascular Research Center, Univ. of Connecticut, School of Medicine, Farmington, CT 06030-1110, USA. ddas@neuron.uchc.edu
Powell
Saul R
SR
Wang
Ping
P
Divald
Andras
A
Nesaretnam
Kalanithi
K
Tosaki
Arpad
A
Cordis
Gerald A
GA
Maulik
Nilanjana
N
Das
Dipak K
DK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D000073878:Palm Oil; D010766:Phosphorylation / Q000187:drug effects; D010938:Plant Oils / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D024508:Tocotrienols / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D016276:Ventricular Function / Q000187:drug effects
D000975:Antioxidants; D002316:Cardiotonic Agents; D010938:Plant Oils; D024508:Tocotrienols; D000073878:Palm Oil; D016392:Proto-Oncogene Proteins pp60(c-src); D046988:Proteasome Endopeptidase Complex