title: Enhanced CD36 expression changes the role of Nrf2 activation from anti-atherogenic to pro-atherogenic in apoE-deficient mice.
abstract: Oxidative stress has been implicated as a causative factor of atherosclerosis. Defense systems against oxidative stress are maintained by radical scavenging antioxidants and/or by regulating the expression of antioxidant genes by activating oxidative stress-sensitive transcription factor: nuclear factor (erythroid-derived 2)-like 2 (Nrf2). We investigated the anti-atherogenic effects of three synthesized compounds (shogaol A: radical scavenging antioxidant activity; shogaol N: Nrf2-activating activity; shogaol N + A: both activities) and curcumin (both activities) in apolipoprotein E (apoE)-deficient mice. We expected compounds with both activities to have additive or synergistic anti-atherogenic effects; however, atherosclerosis was exacerbated significantly by curcumin and slightly by shogaol N + A. Shogaol A, shogaol N, and shogaol N + A showed no significant effect on atherosclerosis development. Immunohistochemical analysis of the aorta revealed that expression of CD36, an Nrf2-regulated gene, was strongly induced by treatment with curcumin. The total antioxidant capacity of plasma collected from mice administered the three compounds was evaluated using a hydrophilic probe, pyranine. Shogaol N or shogaol N + A significantly enhanced the antioxidant capacity of plasma, whereas shogaol A and curcumin did not show this activity. The concentrations of the three shogaol derivatives in plasma were similar (approximately 100 nM), while that of curcumin was much lower. These results suggest that plasma antioxidant capacity is maintained at high levels via Nrf2 activation and that CD36 expression enhances atherosclerosis development.
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan. sawada_hirotaka@kaken.co.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Sawada
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000209:etiology* / Q000517:prevention & control; D018955:CD36 Antigens / Q000096:biosynthesis*; D002210:Caprylates / Q000097:blood / Q000494:pharmacology; D002396:Catechols / Q000097:blood / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007850:Lauric Acids / Q000097:blood / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress; D015854:Up-Regulation
chemical_list: C579625:12-(3-methoxy-4-(methoxymethoxy) phenyl)-10-oxododec-8-enoic acid ethyl ester; C579627:12-(4-hydroxy-3-methoxyphenyl)-10-oxododec-8-enoic acid ethyl ester; C579626:8-(3-(4-hydroxy-3-methoxyphenyl) propanamido) octanoic acid ethyl ester; D000975:Antioxidants; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002210:Caprylates; D002396:Catechols; D016166:Free Radical Scavengers; D007850:Lauric Acids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C040115:shogaol; D003474:Curcumin