Function of NADPH oxidase 1 in pulmonary arterial smooth muscle cells after monocrotaline-induced pulmonary vascular remodeling

Antioxid Redox Signal. 2013 Dec 20;19(18):2213-31. doi: 10.1089/ars.2012.4904. Epub 2013 Jul 20.


Aims: Chronic hypoxia induces pulmonary hypertension (PH) that is concomitant with pulmonary vascular remodeling. Reactive oxygen species (ROS) are thought to play a major role in this. Recent findings suggest that ROS production by NADPH oxidase 4 (Nox4) is important in this remodeling. We investigated whether ROS production by Nox is also important in an inflammatory model of monocrotaline (MCT)-induced PH. We examined ROS production, their possible sources, and their impact on the function of pulmonary arterial smooth muscle cells (PASMC) isolated from MCT-treated and healthy rats.

Results: MCT-PASMC showed increased intracellular superoxide production, migration, and proliferation compared with healthy controls due to increased Nox1 expression. A comparison of PASMC from MCT- and nontreated rats revealed an up-regulation of Sod2, Nrf2, cyclin D1, and matrix metalloproteinase-9 (MMP-9) as well as an increased phosphorylation of cofilin and extracellular signal-regulated kinases (Erk). Expression of Sod2, Nrf2, and cyclin D1 and phosphorylation of cofilin and Erk were Nox1 dependent.

Innovation: The role of ROS in PH is not fully understood. Mitochondria and Nox have been suggested as sources of altered ROS generation in PH, yet it remains unclear whether increased or decreased ROS contributes to the development of PH. Our studies provide evidence that for different triggers of PH, different Nox isoforms regulate proliferation and migration of PASMC.

Conclusion: In contrast to hypoxia-induced PH, Nox1 but not Nox4 is responsible for pathophysiological proliferation and migration of PASMC in an inflammatory model of MCT-induced PH via increased superoxide production. Thus, different Nox isoforms may be targeted in different forms of PH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Male
  • Monocrotaline / pharmacology*
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / metabolism
  • NADH, NADPH Oxidoreductases / metabolism*
  • NADPH Oxidase 1
  • Pulmonary Artery / cytology*
  • Pulmonary Artery / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship


  • Reactive Oxygen Species
  • Monocrotaline
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1
  • NOX1 protein, rat