title: Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase.
abstract: Edaravone, a newly synthesized synthetic radical scavenger, has been identified and adopted as an anti-stroke agent. However, its mechanism and the effect of edaravone on lipoprotein oxidation are not fully understood. Therefore, whether edaravone could suppress oxidation of low-density lipoprotein (LDL) and be involved in the expression of endothelial nitric oxide synthase (eNOS) in relation to anti-atherogenesis by improving and conserving vascular circulation was investigated. We investigated the in vitro effects of edaravone on copper- and endothelial cell-mediated LDL oxidation, and the expression of eNOS in human umbilical vein endothelial cells (HUVEC) modulated by oxidized LDL. The in vivo effect of edaravone on antioxidative effect was also studied in male rats intravenously administered with edaravone. Edaravone apparently inhibited copper- and HUVEC-mediated LDL oxidation at the concentration equivalent to serum concentrations in clinical use. The intravenous administration of edaravone also enhanced serum radical-scavenging property in rats. We tested the effect of edaravone on protein and mRNA expression of eNOS in HUVEC. Edaravone enhanced eNOS expression in HUVEC, presumably because of increased stability of eNOS mRNA, and reversed eNOS expression reduced by oxidized LDL nearly to the control levels. The present study demonstrates for the first time that edaravone increases eNOS expression with the inhibition of LDL oxidation, and that edaravone can reverse oxidized LDL-mediated reduction in eNOS expression in endothelial cells. The preventive action of edaravone from ischemic disease consequence may be attributed to these eNOS up-regulation with decreased oxidation.
authors.affiliation: Division of General Medicine, Department of Internal Medicine, Kashiwa Hospital, Jikei University School of Medicine, 163-1 Kashiwashita, Kashiwa, Chiba 277-8567, Japan. hyoshida@jikei.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kayoko
authors.initials: K
authors.lastname: Sasaki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Namiki
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Norio
authors.initials: N
authors.lastname: Tada
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000097:blood / Q000494:pharmacology*; D007275:Injections, Intravenous; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D001798:Blood Proteins; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D003300:Copper; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000077553:Edaravone; D000983:Antipyrine