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.

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