Targeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPARα Mediated Mechanism

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...

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Bibliographic Details
Published in:	PloS one Vol. 6; no. 2; p. e14665
Main Authors:	Garrido-Urbani, Sarah, Jemelin, Stephane, Deffert, Christine, Carnesecchi, Stéphanie, Basset, Olivier, Szyndralewiez, Cédric, Heitz, Freddy, Page, Patrick, Montet, Xavier, Michalik, Liliane, Arbiser, Jack, Rüegg, Curzio, Krause, Karl Heinz, Imhof, Beat
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 07.02.2011 Public Library of Science (PLoS)
Subjects:	Angiogenesis Angiogenesis Inhibitors - pharmacology Angiogenesis Inhibitors - therapeutic use Animals Cancer Cardiovascular Disorders/Vascular Biology Cell adhesion & migration Cell Biology Cell migration Cell survival Cells, Cultured Cues CYBB protein Endothelial cells Endothelial Cells - drug effects Endothelial Cells - metabolism Female Fibroblasts Gene Knockdown Techniques Gene Targeting Humans Immunoglobulins Immunology Isoforms Kinases Leukocyte migration Localization Medical imaging Metastasis Mice Mice, Inbred C57BL Mice, Knockout Models, Biological Molecular Targeted Therapy NAD(P)H oxidase 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 NF-κB protein NOX4 protein Oncology Oxygen Pathology PPAR alpha - genetics PPAR alpha - physiology Proteins Pyrazoles - pharmacology Pyrazoles - therapeutic use Pyridones - pharmacology Pyridones - therapeutic use Reactive oxygen species Regulators RNA, Small Interfering - pharmacology Rodents Signal Transduction - drug effects Signal Transduction - genetics Signaling Tomography Tumors Switzerland
ISSN:	1932-6203, 1932-6203
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23 Conceived and designed the experiments: SGU KHK BI. Performed the experiments: SGU SJ CD SC OB CS FH PP. Analyzed the data: SGU. Contributed reagents/materials/analysis tools: CD SC OB CS FH PP XM LM JA CR KHK. Wrote the paper: SGU KHK BI.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0014665