title: Vascular peroxidase 1 up regulation by angiotensin II attenuates nitric oxide production through increasing asymmetrical dimethylarginine in HUVECs.
abstract: Asymmetric dimethylarginine (ADMA), the endogenous inhibitor of nitric oxide synthase, contributes to endothelial dysfunction and subsequent cardiovascular events including hypertension. Vascular peroxidase 1 (VPO1) is a novel heme-containing peroxidase that uses hydrogen peroxide (H2O2) generated from co-expressed nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to catalyze peroxidative reactions. Our previous study revealed a clear connection between VPO1 gene expression and endothelial dysfunction in spontaneously hypertensive rats. In the present study, we explored whether VPO1 participates in endothelial dysfunction during hypertension by increasing ADMA production. Spontaneously hypertensive rats displayed impaired endothelium-dependent relaxation, decreased eNOS expression and nitric oxide production, significantly increased VPO1 expression in both plasma and aorta tissue, and an increased ADMA level in plasma. In cultured endothelial cells, angiotensin II increased the ADMA level by inhibiting dimethylarginine dimethylaminohydrolase activity, which was inhibited by knockdown of VPO1 using small hairpin RNA. Moreover, the NADPH oxidase inhibitor and the hydrogen peroxide scavenger attenuated angiotensin II-mediated up-regulation of VPO1 and generation of hypochlorous acid. Furthermore, VPO1-derived hypochlorous acid suppressed recombinant dimethylarginine dimethylaminohydrolase activity and increased ADMA production. VPO1 plays a critical role in ADMA production via H2O2-VPO1-hypochlorous acid pathways, which may contribute to endothelial dysfunction in hypertension.
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Luyao
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zaixin
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Guogang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China. Electronic address: xysrz2010@sina.com.
authors.forename: Ruizheng
authors.initials: R
authors.lastname: Shi
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006420:Hemeproteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D006997:Hypochlorous Acid / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000378:metabolism; D015854:Up-Regulation; D000097423:Peroxidasin
chemical_list: D000581:Amidohydrolases; D000804:Angiotensin II; D001120:Arginine; D006420:Hemeproteins; D006861:Hydrogen Peroxide; D006997:Hypochlorous Acid; D019255:NADPH Oxidases; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D010544:Peroxidases; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C018524:N,N-dimethylarginine; C573339:vascular peroxidase, rat; C535215:PXDN protein, human; D000097423:Peroxidasin; C496316:Nos3 protein, rat; C059999:dimethylargininase
keywords: Endothelial dysfunction; hypertension; nicotinamide adenine dinucleotide phosphate oxidase