title: Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress.
abstract: The present study explored the possibility that estrogen enhances the inhibitory effect of an angiotensin II type-1 (AT1) receptor blocker (ARB), olmesartan, on atherosclerosis, focusing on oxidative stress using apolipoprotein E knockout mice (ApoEKO). After 6 weeks on a high-cholesterol diet, marked atherosclerotic lesion formation with an increase in oxidative stress, such as superoxide production, NAD(P)H oxidase activity and expression of p47phox mRNA and rac-1 mRNA, were observed in the proximal aorta in both male and female ApoEKO mice, whereas these changes were less marked in female mice. Ovariectomy enhanced these parameters, the changes of which were reversed by 17beta-estradiol (80 microg/kg per day) replacement. Treatment with olmesartan (3 mg/kg per day) significantly inhibited oxidative stress and atherosclerosis, whereas its inhibitory effects were more marked in female than in male or ovariectomized mice. Smaller doses of olmesartan (0.5 mg/kg per day) or 17beta-estradiol (20 microg/kg per day) did not influence atherosclerosis and oxidative stress in ovariectomized mice, whereas co-administration of olmesartan and 17beta-estradiol at these doses attenuated these parameters. An angiotensin-converting enzyme (ACE) inhibitor, temocapril, also inhibited atherosclerotic changes similarly to olmesartan. Moreover, angiotensin II-mediated activation of NAD(P)H oxidase in cultured vascular smooth muscle cells was attenuated by 17beta-estradiol. These results indicate that estrogen and an ARB synergistically attenuate atherosclerosis at least partly via inhibition of oxidative stress.
authors.affiliation: Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shigenobu, Ehime, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Huan-Sheng
authors.initials: HS
authors.lastname: Li
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ide
authors.forename: Midori
authors.initials: M
authors.lastname: Okumura
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D004958:Estradiol; C437965:olmesartan; D019255:NADPH Oxidases