title: Effects of vitamin E on peroxisome proliferator-activated receptor γ and nuclear factor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosis.
abstract: Atherosclerosis and associated cardiovascular complications such as stroke and myocardial infarction are major causes of morbidity and mortality. We have previously reported a significant increase in mRNA levels of the scavenger receptor CD36 in aortae of cholesterol-fed rabbits and shown that vitamin E treatment attenuated increased CD36 mRNA expression. In the present study, we further investigated the redox signaling pathways associated with protection against atherogenesis induced by high dietary cholesterol and correlated these with CD36 expression and the effects of vitamin E supplementation in a rabbit model. Male albino rabbits were assigned to either a control group fed with a low vitamin E diet alone or a test group fed with a low vitamin E diet containing 2% cholesterol in the absence or presence of daily intramuscular injections of vitamin E (50mg/kg). To elucidate the mechanisms by which vitamin E supplementation alters the effects of hypercholesterolemia in rabbit aortae, we measured peroxisome proliferator-activated receptor γ (PPARγ), ATP-binding cassette transporter A1 (ABCA1), and matrix metalloproteinase-1 (MMP-1) mRNA levels by quantitative RT-PCR and the expression of MMP-1, nuclear factor-erythroid 2-related factor 2 (Nrf2), and glutathione S-transferase α (GSTα) protein by immunoblotting. The increased MMP-1 and decreased GSTα expression observed suggests that a cholesterol-rich diet contributes to the development of atherosclerosis, whereas vitamin E supplementation affords protection by decreasing MMP-1 and increasing PPARγ, GSTα, and ABCA1 levels in aortae of rabbits fed a cholesterol-rich diet. Notably, protein expression of Nrf2, the antioxidant transcription factor, was increased in both the cholesterol-fed and the vitamin E-supplemented groups. Although Nrf2 activation can promote CD36-mediated cholesterol uptake by macrophages, the increased induction of Nrf2-mediated antioxidant genes is likely to contribute to decreased lesion progression. Thus, our study demonstrates that Nrf2 can mediate both pro- and antiatherosclerotic effects.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center, Marmara University, 34668 Haydarpasa, Istanbul, Turkey.
authors.forename: Perinur
authors.initials: P
authors.lastname: Bozaykut
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center, Marmara University, 34668 Haydarpasa, Istanbul, Turkey.
authors.forename: Betul
authors.initials: B
authors.lastname: Karademir
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center, Marmara University, 34668 Haydarpasa, Istanbul, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Yazgan
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center, Marmara University, 34668 Haydarpasa, Istanbul, Turkey.
authors.forename: Erdi
authors.initials: E
authors.lastname: Sozen
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King's College London, London SE1 9NH, UK.
authors.forename: Richard C M
authors.initials: RC
authors.lastname: Siow
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King's College London, London SE1 9NH, UK.
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Mann
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center, Marmara University, 34668 Haydarpasa, Istanbul, Turkey. Electronic address: nkozer@marmara.edu.tr.
authors.forename: Nesrin Kartal
authors.initials: NK
authors.lastname: Ozer
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000096:biosynthesis; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000473:pathology; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage*
chemical_list: D002791:Cholesterol, Dietary; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; D047495:PPAR gamma; D014810:Vitamin E; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D020781:Matrix Metalloproteinase 1
keywords: Atherosclerosis; Free radicals; Hypercholesterolemia; Nrf2; PPARγ; Redox signaling; Vitamin E