NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts.
The NADPH oxidases are involved in vascular remodeling processes and oxygen sensing. Hypoxia-induced pulmonary arterial remodeling results in thickening of the vessel wall and reduction of the area of vessel lumen, leading to pulmonary hypertension and cor pulmonale. The proliferation of pulmonary artery adventitial fibroblasts (PAFB) is critically involved in this process. In this study, we analyzed the role of the non-phagocytic NADPH oxidase subunits NOX1 and NOX4 in PAFB. NOX4 was predominantly expressed in comparison to NOX1 at mRNA levels. Under hypoxic conditions, NOX4 was significantly upregulated at mRNA and protein levels. Silencing of NOX4 by siRNA caused reduction of ROS levels under both normoxic and hypoxic (24 h) conditions and suppressed the significant hypoxic-induced ROS increase. PAFB proliferation was significantly decreased in cells transfected with NOX4 siRNA, whereas apoptosis was enhanced. Also, the expression of NOX4 was studied in PAFB isolated from the lungs of patients with idiopathic pulmonary arterial hypertension (IPAH). Interestingly, a significant increase of NOX4 mRNA expression was observed under hypoxic conditions in PAFB from the lungs with IPAH compared to healthy donors. In conclusion, NOX4 maintains ROS levels under normoxic and hypoxic conditions and enhances proliferation and inhibits apoptosis of PAFB.
Li
Shu
S
University of Giessen Lung Center, Medical Clinic II, Giessen, Germany.
Tabar
Sarvenaz Shafiei
SS
Malec
Viktor
V
Eul
Bastian G
BG
Klepetko
Walter
W
Weissmann
Norbert
N
Grimminger
Friedrich
F
Seeger
Werner
W
Rose
Frank
F
Hänze
Jörg
J
D017209:Apoptosis / Q000502:physiology; D002374:Catalase / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D002374:Catalase; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human; D010100:Oxygen