Nox2 regulates endothelial cell cycle arrest and apoptosis via p21cip1 and p53

Free Radic Biol Med. 2007 Sep 15;43(6):976-86. doi: 10.1016/j.freeradbiomed.2007.06.001. Epub 2007 Jun 13.

Abstract

Endothelial cells (EC) express constitutively two major isoforms (Nox2 and Nox4) of the catalytic subunit of NADPH oxidase, which is a major source of endothelial reactive oxygen species. However, the individual roles of these Noxes in endothelial function remain unclear. We have investigated the role of Nox2 in nutrient deprivation-induced cell cycle arrest and apoptosis. In proliferating human dermal microvascular EC, Nox2 mRNA expression was low relative to Nox4 (Nox2:Nox4 approximately 1:13), but was upregulated 24 h after starvation and increased to 8+/-3.5-fold at 36 h of starvation. Accompanying the upregulation of Nox2, there was a 2.28+/-0.18-fold increase in O2.- production, a dramatic induction of p21cip1 and p53, cell cycle arrest, and the onset of apoptosis (all p<0.05). All these changes were inhibited significantly by in vitro deletion of Nox2 expression and in coronary microvascular EC isolated from Nox2 knockout mice. In Nox2 knockout cells, although there was a 3.8+/-0.5-fold increase in Nox4 mRNA expression after 36 h of starvation (p<0.01), neither O2.- production nor the p21cip1 or p53 expression was increased significantly and only 0.46% of cells were apoptotic. In conclusion, Nox2-derived O2.-, through the modulation of p21cip1 and p53 expression, participates in endothelial cell cycle regulation and apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / genetics
  • Cell Cycle* / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA, Antisense / pharmacology
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / enzymology
  • Humans
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • NADPH Oxidase 1
  • NADPH Oxidase 2
  • NADPH Oxidase 4
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Oxidative Stress
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA, Antisense
  • Membrane Glycoproteins
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • CYBB protein, human
  • NADPH Oxidase 1
  • NADPH Oxidase 2
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX1 protein, human
  • NOX4 protein, human
  • neutrophil cytosolic factor 1