title: Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes.
abstract: 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.
authors.affiliation: Cardiovascular Research Center, Univ. of Connecticut, School of Medicine, Farmington, CT 06030-1110, USA. ddas@neuron.uchc.edu
authors.forename: Samarjit
authors.initials: S
authors.lastname: Das
authors.forename: Saul R
authors.initials: SR
authors.lastname: Powell
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Andras
authors.initials: A
authors.lastname: Divald
authors.forename: Kalanithi
authors.initials: K
authors.lastname: Nesaretnam
authors.forename: Arpad
authors.initials: A
authors.lastname: Tosaki
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Cordis
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
mesh_terms: 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
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D010938:Plant Oils; D024508:Tocotrienols; D000073878:Palm Oil; D016392:Proto-Oncogene Proteins pp60(c-src); D046988:Proteasome Endopeptidase Complex