Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species

Feng Chen, Scott Barman, Yanfang Yu, Steven Haigh, Yusi Wang, Huijuan Dou, Zsolt Bagi, Weihong Han, Yunchao Su, David J.R. Fulton

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)201-213
Number of pages13
JournalFree Radical Biology and Medicine
Volume73
DOIs
StatePublished - Aug 2014

Keywords

  • Caveolin-1
  • Free radicals
  • NADPH oxidase
  • Pulmonary hypertension
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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