title: Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor.
abstract: Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH.
authors.affiliation: Departments of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. saogura-tky@umin.ac.jp
authors.forename: Sayoko
authors.initials: S
authors.lastname: Ogura
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Shengyu
authors.initials: S
authors.lastname: Mu
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kawakami-Mori
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Yuzaburo
authors.initials: Y
authors.lastname: Uetake
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; C002744:3-nitrotyrosine; D014443:Tyrosine; D019255:NADPH Oxidases
keywords: NADPH oxidase; hypoxia; low-density lipoprotein receptor-1; oxidative stress; pulmonary hypertension