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PMID: 22797809 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Pathological neoangiogenesis depends on oxidative stress regulation by ATM.

Nature medicine ·Vol. 18 ·No. 8 ·2012-08-00 ·Pages 1208-16

Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T, Kubota Y

Abstract

The ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), acts as a barrier to cellular senescence and tumorigenesis. Aside from DDR signaling, ATM also functions in oxidative defense. Here we show that Atm in mice is activated specifically in immature vessels in response to the accumulation of reactive oxygen species (ROS). Global or endothelial-specific Atm deficiency in mice blocked pathological neoangiogenesis in the retina. This block resulted from increased amounts of ROS and excessive activation of the mitogen activated kinase p38α rather than from defects in the canonical DDR pathway. Atm deficiency also lowered tumor angiogenesis and enhanced the antiangiogenic action of vascular endothelial growth factor (Vegf) blockade. These data suggest that pathological neoangiogenesis requires ATM-mediated oxidative defense and that agents that promote excessive ROS generation may have beneficial effects in the treatment of neovascular disease.

MeSH Terms
Acetylcysteine/pharmacology,therapeutic use Animals Antioxidants/pharmacology,therapeutic use Apoptosis Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/deficiency,genetics,physiology Cells, Cultured/drug effects,metabolism DNA Repair DNA-Binding Proteins/deficiency,genetics,physiology Endothelium, Vascular/physiopathology Enzyme Activation Eye Proteins/physiology Female Humans Hydrogen Peroxide/antagonists & inhibitors,toxicity Ischemia/drug therapy,pathology,physiopathology Lipid Peroxidation/drug effects Male Melanoma, Experimental/blood supply Mice Mice, Inbred C57BL Mice, Knockout Morpholines/pharmacology Neovascularization, Pathologic/physiopathology,prevention & control Oxidative Stress/physiology Protein Serine-Threonine Kinases/deficiency,genetics,physiology Pyrones/pharmacology Reactive Oxygen Species/metabolism Retinal Neovascularization/pathology,physiopathology,prevention & control Retinal Vessels/drug effects,pathology Signal Transduction/drug effects Tumor Suppressor Proteins/deficiency,genetics,physiology Vascular Endothelial Growth Factor A/antagonists & inhibitors,physiology p38 Mitogen-Activated Protein Kinases/physiology
Chemicals
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one Antioxidants Cell Cycle Proteins DNA-Binding Proteins Eye Proteins Morpholines Pyrones Reactive Oxygen Species Tumor Suppressor Proteins Vascular Endothelial Growth Factor A vascular endothelial growth factor A, mouse Hydrogen Peroxide ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Acetylcysteine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Okuno Yuji
Center for Integrated Medical Research, School of Medicine, Keio University, Tokyo, Japan.
Nakamura-Ishizu Ayako
Otsu Kinya
Suda Toshio
Kubota Yoshiaki
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2846
Published
2012-08-00
Epub
2012-00-15
Pages
1208-16
Language
English
Region
United States
NLM ID
9502015
Subset
IM
External Links
PubMed source DOI: 10.1038/nm.2846 View journal details
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