TY - JOUR
T1 - Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species
AU - Chen, Feng
AU - Barman, Scott
AU - Yu, Yanfang
AU - Haigh, Steven
AU - Wang, Yusi
AU - Dou, Huijuan
AU - Bagi, Zsolt
AU - Han, Weihong
AU - Su, Yunchao
AU - Fulton, David J.R.
N1 - Funding Information:
The authors gratefully acknowledge the technical assistance of Louise Meadows and Yevgeniy Kovalenkov. This work was supported by GRU Pilot Study Research Program Award 0053A (S.A.B. and D.F.), GRU Extramural Success Award 00006A (S.A.B. and D.F.), R01-HL-092446 (D.F.), P01-HL-0101902 (D.F.), and a postdoctoral fellowship from the American Heart Association (13POST14800025 to F.C.).
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
KW - Caveolin-1
KW - Free radicals
KW - NADPH oxidase
KW - Pulmonary hypertension
KW - Reactive oxygen species
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U2 - 10.1016/j.freeradbiomed.2014.04.029
DO - 10.1016/j.freeradbiomed.2014.04.029
M3 - Article
C2 - 24835767
AN - SCOPUS:84902248613
SN - 0891-5849
VL - 73
SP - 201
EP - 213
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -