title: Treatment with n-3 polyunsaturated fatty acids reverses endothelial dysfunction and oxidative stress in experimental menopause.
abstract: Menopause is associated with endothelial dysfunction and oxidative stress. In this condition, reduced n-3 polyunsaturated fatty acids (n-3 PUFAs) contribute to cardiovascular disease. We investigated whether treatment with n-3 PUFA reverses endothelial dysfunction and oxidative stress in experimental menopause. Thirty female rats underwent either sham-surgery or bilateral ovariectomy or bilateral ovariectomy+oral n-3 PUFA (0.8 g kg(-1) day(-1) for 2 months). Ovariectomy caused endothelial dysfunction to acetylcholine, which was reversed by superoxide scavenger Tiron. Erythrocyte membrane lipid composition was characterized by reduced n-3 PUFA total content and omega-3 index, and by concomitant increase in n-6:n-3 PUFA ratio. Ovariectomy-related oxidative stress, demonstrated by both enhanced superoxide production and 3-nitrotyrosine expression in aorta, was associated with increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX-4 protein expression. Endothelial nitric oxide synthase (eNOS) functional inhibition by l-NG-nitroarginine methyl ester, protein expression and activity did not change. In ovariectomized rats, treatment with n-3 PUFA increased n-3 PUFA total content and omega-3 index and decreased n-6:n-3 PUFA ratio in erythrocyte membrane, reversed vascular oxidative stress, endothelial dysfunction, aortic 3-nitrotyrosine and markedly lowered NOX-4 protein expression; eNOS protein expression also increased, paralleled by reversal of inhibitory binding to Caveolin-1, while ex-vivo functional inhibition and NOS synthesis were unchanged. These findings demonstrate in vivo a therapeutic benefit of n-3 PUFA on menopause-associated endothelial dysfunction by reversal of alterations in membrane lipid composition induced by ovariectomy and by reduction of vascular oxidative stress. In this setting they also identify NOX-4 as a potential target to reduce oxidative stress-mediated vascular complications.
authors.affiliation: U.C.O. Clinica Medica Generale e Terapia Medica, DSMCS, University of Trieste, Trieste, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gortan Cappellari
authors.forename: Pasquale
authors.initials: P
authors.lastname: Losurdo
authors.forename: Sara
authors.initials: S
authors.lastname: Mazzucco
authors.forename: Emiliano
authors.initials: E
authors.lastname: Panizon
authors.forename: Mitja
authors.initials: M
authors.lastname: Jevnicar
authors.forename: Loredana
authors.initials: L
authors.lastname: Macaluso
authors.forename: Bruno
authors.initials: B
authors.lastname: Fabris
authors.forename: Rocco
authors.initials: R
authors.lastname: Barazzoni
authors.forename: Gianni
authors.initials: G
authors.lastname: Biolo
authors.forename: Renzo
authors.initials: R
authors.lastname: Carretta
authors.forename: Michela
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D051242:Caveolin 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D008593:Menopause / Q000187:drug effects* / Q000502:physiology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015415:Biomarkers; C495537:Cav1 protein, rat; D051242:Caveolin 1; D015525:Fatty Acids, Omega-3; D016166:Free Radical Scavengers; D008563:Membrane Lipids; D013481:Superoxides; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat