Original ContributionEffects of vitamin E on peroxisome proliferator-activated receptor γ and nuclear factor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosis
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Animals and diets
All experimental procedures were approved by the Marmara University Animal Care and Use Committee, Istanbul (Protocol 062008). Twenty-one male albino rabbits (2–3 months of age) were assigned randomly to three groups, which were fed: (i) vitamin E-poor diet, (ii) vitamin E poor-diet containing 2% cholesterol, or (iii) vitamin E-poor diet containing 2% cholesterol with daily intramuscular injections of vitamin E (50 mg/kg). After 4 weeks, after overnight fasting, rabbits were anesthetized using 50
Effects of cholesterol and vitamin E supplementation on blood serum levels
Supplementation with 2% cholesterol for 4 weeks resulted in ~30-fold increase in serum cholesterol in the cholesterol and cholesterol + vitamin E groups compared to the control group (Table 1). Intramuscular vitamin E injections increased serum vitamin E levels ~11-fold in the cholesterol + vitamin E group (Table 1). In the cholesterol group, serum vitamin E levels appeared to increase, mostly as vitamin E is a fat-soluble vitamin carried by LDL cholesterol in blood, but the values corrected
Discussion
A high-cholesterol diet leads to metabolic changes involving endothelial damage, an increase in extracellular matrix synthesis, smooth muscle cell proliferation, and altered antioxidant and pro-oxidant enzyme activity related to the progression of atherosclerotic lesions. To investigate the relationship between hypercholesterolemia and atherogenesis in vivo, feeding rabbits a 2% cholesterol-containing diet for 4 weeks was found to be sufficient to elicit formation of atherosclerotic lesions in
Conclusions
In summary, our findings demonstrate that a high-cholesterol diet significantly enhances lipid accumulation via Nrf2-mediated induction of CD36 expression during atherogenesis. We also provided evidence for the role of vitamin E supplementation on gene expression through the upregulation of PPARγ and Nrf2 and induction of their downstream targets ABCA1 and GSTα, respectively, and through inhibition of MMP-1. ABCA1 upregulation results in cholesterol efflux from macrophages and inhibition of
Acknowledgments
This study was supported by COST B35 Action; TUBITAK (106S121); Marmara University Research Funds SAG-C-YLP-130511-014, SAG-C-YLP-070211-0038, SAG-C-YLP-050608-0125; and Heart Research UK (G.E.M., R.C.M.S.).
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