title: Nox2 regulates endothelial cell cycle arrest and apoptosis via p21cip1 and p53.
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.
authors: Cardiovascular Research Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. j.li@surrey.ac.uk
authors: Jian-Mei
authors: JM
authors: Li
authors: Lampson M
authors: LM
authors: Fan
authors: Vinoj T
authors: VT
authors: George
authors: Gavin
authors: G
authors: Brooks
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D016373:DNA, Antisense / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016373:DNA, Antisense; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C056558:CYBB protein, human; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human; C060505:neutrophil cytosolic factor 1
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