Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species.
Changes in the expression and function of caveolin-1 (Cav-1) have been proposed as a pathogenic mechanism underlying many cardiovascular diseases. Cav-1 binds to and regulates the activity of numerous signaling proteins via interactions with its scaffolding domain. In endothelial cells, Cav-1 has been shown to reduce reactive oxygen species (ROS) production, but whether Cav-1 regulates the activity of NADPH oxidases (Noxes), a major source of cellular ROS, has not yet been shown. Herein, we show that Cav-1 is primarily expressed in the endothelium and adventitia of pulmonary arteries (PAs) and that Cav-1 expression is reduced in isolated PAs from multiple models of pulmonary artery hypertension (PH). Reduced Cav-1 expression correlates with increased ROS production in the adventitia of hypertensive PA. In vitro experiments revealed a significant ability of Cav-1 and its scaffolding domain to inhibit Nox1-5 activity and it was also found that Cav-1 binds to Nox5 and Nox2 but not Nox4. In addition to posttranslational actions, in primary cells, Cav-1 represses the mRNA and protein expression of Nox2 and Nox4 through inhibition of the NF-κB pathway. Last, in a mouse hypoxia model, the genetic ablation of Cav-1 increased the expression of Nox2 and Nox4 and exacerbated PH. Together, these results suggest that Cav-1 is a negative regulator of Nox function via two distinct mechanisms, acutely through direct binding and chronically through alteration of expression levels. Accordingly, the loss of Cav-1 expression in cardiovascular diseases such as PH may account for the increased Nox activity and greater production of ROS.
Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Vascular Biology Center and Georgia Regents University, Augusta, GA 30912, USA. Electronic address: fchen@gru.edu.
Feng
F
Chen
Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA.
Scott
S
Barman
Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Vascular Biology Center and Georgia Regents University, Augusta, GA 30912, USA.
Yanfang
Y
Yu
Vascular Biology Center and Georgia Regents University, Augusta, GA 30912, USA.
Steven
S
Haigh
Vascular Biology Center and Georgia Regents University, Augusta, GA 30912, USA.
Yusi
Y
Wang
Stephen M
SM
Black
Ruslan
R
Rafikov
Huijuan
H
Dou
Vascular Biology Center and Georgia Regents University, Augusta, GA 30912, USA.
Zsolt
Z
Bagi
Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA.
Weihong
W
Han
Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA.
Yunchao
Y
Su
Vascular Biology Center and Georgia Regents University, Augusta, GA 30912, USA; Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: dfulton@gru.edu.
David J R
DJ
Fulton
D063194:Adventitia / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D051242:Caveolin 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004727:Endothelium / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011651:Pulmonary Artery / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D051242:Caveolin 1; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases
Caveolin-1; Free radicals; NADPH oxidase; Pulmonary hypertension; Reactive oxygen species