title: Tocotrienols confer resistance to ischemia in hypercholesterolemic hearts: insight with genomics.
abstract: Most clinical trials with vitamin E could not lower cholesterol and thus, have been deemed unsuccessful. Recently, tocotrienols, isomers of vitamin E have been found to lower LDL levels. To explore if tocotrienols could be the drug target for vitamin E, rabbits were kept on cholesterol diet for 60 days supplemented with tocotrienol-α, tocotrienol-δ, and tocotrienol-γ for the last 30 days. The serum cholesterol levels (in mmol/l) were 24.4 (tocotrienol-α), 34.9 (tocotrienol-δ), 19.8 (tocotrienol-γ) vs. 39.7 (control). Left ventricular function including aortic flow and developed pressure exhibited significantly improved recovery with tocotrienol-γ and -α, but not with tocotrienol-δ. The myocardial infarct size showed a similar pattern: 33% (tocotrienol-α), 23% (tocotrienol-γ), and 47% (tocotrienol-δ). To examine the molecular mechanisms of cardioprotective effects, gene expression profile was determined using Atlas 1.2/1.2II followed by determination of gene profiles using PedQuest 8.3 software. Based on genomic profiles, the following cholesterol-related proteins were examined: FABP, TGF-β (cholesterol suppresses TGF-β), ET-1 (increased by hypercholesterolemia), SPOT 14 (linked with hypercholesterolemia), and matrix metalloproteinase (MMP) 2 and MMP9 (cholesterol regulates MMP2 and MMP9 expression) in the heart. Consistent with the cardioprotective effects of tocotrienol-α and -γ, these two isomers reduced ET-1, decreased MMP2 and MM9, increased TGF-β and reduced SPOT 14, while tocotrienol-δ had no effects. The results of the present study demonstrate that the two isomers of tocotrienols, α and γ, render the hypercholesterolemic hearts resistant to ischemic reperfusion injury by lowering several hypercholesterolemic proteins including MMP2, MMP9, ET-1, and SPOT 14 and upregulating TGF-β.
authors.affiliation: Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
authors.forename: Somak
authors.initials: S
authors.lastname: Das
authors.forename: Subhendu
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Istvan
authors.initials: I
authors.lastname: Lekli
authors.forename: Narasimman
authors.initials: N
authors.lastname: Gurusamy
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Bardhan
authors.forename: Utpal
authors.initials: U
authors.lastname: Raychoudhury
authors.forename: Runu
authors.initials: R
authors.lastname: Chakravarty
authors.forename: Sandip
authors.initials: S
authors.lastname: Banerji
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D002839:Chromans / Q000627:therapeutic use*; D059305:Diet, High-Fat; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D002316:Cardiotonic Agents; D002839:Chromans; D019332:Endothelin-1; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D014810:Vitamin E; C013649:plastochromanol 8; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9