Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism

Sarah Garrido-Urbani; Stephane Jemelin; Christine Deffert; Stéphanie Carnesecchi; Olivier Basset; Cédric Szyndralewiez; Freddy Heitz; Patrick Page; Xavier Montet; Liliane Michalik; Jack Arbiser; Curzio Rüegg; Karl Heinz Krause; Beat A Imhof

doi:10.1371/journal.pone.0014665

Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism

PLoS One. 2011 Feb 7;6(2):e14665. doi: 10.1371/journal.pone.0014665.

Authors

Sarah Garrido-Urbani¹, Stephane Jemelin, Christine Deffert, Stéphanie Carnesecchi, Olivier Basset, Cédric Szyndralewiez, Freddy Heitz, Patrick Page, Xavier Montet, Liliane Michalik, Jack Arbiser, Curzio Rüegg, Karl Heinz Krause, Beat A Imhof

Affiliation

¹ Department of Pathology and Immunology, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.

Abstract

Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / pharmacology
Angiogenesis Inhibitors / therapeutic use
Animals
Cells, Cultured
Endothelial Cells / drug effects
Endothelial Cells / metabolism*
Female
Gene Knockdown Techniques
Gene Targeting
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Molecular Targeted Therapy
NADH, NADPH Oxidoreductases / antagonists & inhibitors
NADH, NADPH Oxidoreductases / genetics*
NADH, NADPH Oxidoreductases / physiology
NADPH Oxidase 1
Neoplasms / blood supply*
Neoplasms / drug therapy
Neoplasms / genetics
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / genetics*
PPAR alpha / genetics
PPAR alpha / physiology*
Pyrazoles / pharmacology
Pyrazoles / therapeutic use
Pyridones / pharmacology
Pyridones / therapeutic use
RNA, Small Interfering / pharmacology
Signal Transduction / drug effects
Signal Transduction / genetics

Substances

2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione
Angiogenesis Inhibitors
PPAR alpha
Pyrazoles
Pyridones
RNA, Small Interfering
NADH, NADPH Oxidoreductases
NADPH Oxidase 1
NOX1 protein, mouse