title: 17beta-Estradiol reverses shear-stress-mediated low density lipoprotein modifications.
abstract: Within arterial bifurcations or branching points, oscillatory shear stress (OSS) induces oxidative stress mainly via the reduced nicotinamide adenine dinucleodtide phosphate (NADPH) oxidase system. It is unknown whether 17beta-estradiol (E(2)) can regulate OSS-mediated low-density lipoprotein (LDL) modifications. Bovine aortic endothelial cells were pretreated with E(2) at 5 nmol/L, followed by exposure to OSS (0 +/- 3.0 dynes/cm(2) s and 60 cycles/min) in a flow system. E(2) decreased OSS-mediated NADPH oxidase mRNA expression, and E(2)-mediated (.-)NO production was mitigated by the NO synthase inhibitor N(G)-nitro-l-argenine methyl ester. The rates of O(2)(-.) production in response to OSS increased steadily as determined by superoxide-dismutase-inhibited ferricytochrome c reduction; whereas, pretreatment with E(2) decreased OSS-mediated O(2)(-.) production (n = 4, p < 0.05). In the presence of native LDL (50 microg/mL), E(2) also significantly reversed OSS-mediated LDL oxidation as determined by high-performance liquid chromatography. In the presence of O(2)(-.) donor, xanthine oxidase (XO), E(2) further reversed XO-induced LDL lipid peroxidation (n = 3, p < 0.001). Mass spectra acquired in the m/z 400-1800 range, revealed XO-mediated LDL protein nitration involving tyrosine 2535 in the alpha-2 domains, whereas pretreatment with E(2) reversed nitration, as supported by the changes in nitrotyrosine intensities. Thus, E(2) plays an indirect antioxidative role. In addition to upregulation of endothelial (.-)NO synthase and downregulation of Nox4 expression, E(2) influences LDL modifications via lipid peroxidation and protein nitration.
authors.affiliation: Department of Biomedical Engineering and Cardiovascular Medicine, Atherosclerosis Research Unit, University of Southern California, Los Angeles, CA 90081, USA.
authors.forename: Juliana
authors.initials: J
authors.lastname: Hwang
authors.forename: Mahsa
authors.initials: M
authors.lastname: Rouhanizadeh
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Hamilton
authors.forename: Tiantian C
authors.initials: TC
authors.lastname: Lin
authors.forename: Jason P
authors.initials: JP
authors.lastname: Eiserich
authors.forename: Howard N
authors.initials: HN
authors.lastname: Hodis
authors.forename: Tzung K
authors.initials: TK
authors.lastname: Hsiai
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004958:Estradiol / Q000737:chemistry*; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry*; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases