title: Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia.
abstract: Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (N(ω)-hydroxy-nor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH.
authors.affiliation: 1 Department of Forensic Medicine, Graduate School of Medicine and.
authors.forename: Akina
authors.initials: A
authors.lastname: Nara
authors.affiliation: 1 Department of Forensic Medicine, Graduate School of Medicine and.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nagai
authors.affiliation: 1 Department of Forensic Medicine, Graduate School of Medicine and.
authors.forename: Kaori
authors.initials: K
authors.lastname: Shintani-Ishida
authors.affiliation: 1 Department of Forensic Medicine, Graduate School of Medicine and.|2 Division of Laboratory Medicine, Department of Pathology and Microbiology, Faculty of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Ogura
authors.affiliation: 3 Department of Clinical Laboratory, Faculty of Medicine, the University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.affiliation: 4 Department of Respiratory Medicine, Tokai University School of Medicine, Kanagawa, Japan; and.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kuwahira
authors.affiliation: 5 Department of Cardiac Physiology, National Cerebral & Cardiovascular Center, Osaka, Japan.
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.affiliation: 1 Department of Forensic Medicine, Graduate School of Medicine and.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000375:Aging; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D015687:Cell Hypoxia; D004789:Enzyme Activation; D006973:Hypertension / Q000201:enzymology*; D008168:Lung / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011651:Pulmonary Artery / Q000201:enzymology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D009566:Nitrates; D009573:Nitrites; C002744:3-nitrotyrosine; D014443:Tyrosine; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001119:Arginase
keywords: age; arginase; intermittent hypoxia; pulmonary arterial hypertension; sleep apnea syndrome