title: Nicorandil prevents sirolimus-induced production of reactive oxygen species, endothelial dysfunction, and thrombus formation.
abstract: Sirolimus (SRL) is widely used to prevent restenosis after percutaneous coronary intervention. However, its beneficial effect is hampered by complications of thrombosis. Several studies imply that reactive oxygen species (ROS) play a critical role in endothelial dysfunction and thrombus formation. The present study investigated the protective effect of nicorandil (NIC), an anti-angina agent, on SRL-associated thrombosis. In human coronary artery endothelial cells (HCAECs), SRL stimulated ROS production, which was prevented by co-treatment with NIC. The preventive effect of NIC on ROS was abolished by 5-hydroxydecanoate but not by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. NIC also inhibited SRL-induced up-regulation of NADPH oxidase subunit p22(phox) mRNA. Co-treatment with NIC and SRL significantly up-regulated superoxide dismutase 2. NIC treatment significantly improved SRL-induced decrease in viability of HCAECs. The functional relevance of the preventive effects of NIC on SRL-induced ROS production and impairment of endothelial viability was investigated in a mouse model of thrombosis. Pretreatment with NIC inhibited the SRL-induced acceleration of FeCl3-initiated thrombus formation and ROS production in the testicular arteries of mice. In conclusion, NIC prevented SRL-induced thrombus formation, presumably due to the reduction of ROS and to endothelial protection. The therapeutic efficacy of NIC could represent an additional option in the prevention of SRL-related thrombosis.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Aizawa
authors.affiliation: Teaching and Research Support Center, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
authors.forename: Youko
authors.initials: Y
authors.lastname: Takahari
authors.affiliation: Department of Physiology, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Higashijima
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Serizawa
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ishizuka
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Endo
authors.affiliation: Department of Physiology, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Fukuyama
authors.affiliation: Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan. Electronic address: khirano@med.kagawa-u.ac.jp.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirano
authors.affiliation: Department of Physiology, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ishida
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001158:Arteries; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D019255:NADPH Oxidases / Q000378:metabolism; D020108:Nicorandil / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020123:Sirolimus / Q000009:adverse effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D013737:Testis / Q000098:blood supply; D013927:Thrombosis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D015854:Up-Regulation / Q000187:drug effects; D000099156:Superoxide Dismutase 2
chemical_list: D000889:Anti-Arrhythmia Agents; D019255:NADPH Oxidases; D020108:Nicorandil; D017382:Reactive Oxygen Species; D020123:Sirolimus; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: Endothelial cells; Nicorandil; Reactive oxygen species; Sirolimus; Thrombosis