Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration

Aims In atherosclerosis and restenosis, vascular smooth muscle cells (SMCs) migrate into the subendothelial space and proliferate, contributing to neointimal formation. The goal of this study was to define the signalling pathway by which Nox1 NAPDH oxidase mediates SMC migration. Methods and results...

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Bibliographic Details
Published in:Cardiovascular research 2012-03, Vol.93 (3), p.406-413
Main Authors: Jagadeesha, Dammanahalli K., Takapoo, Maysam, Banfi, Botond, Bhalla, Ramesh C., Miller, Francis J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cadherins - metabolism
Cardiology. Vascular system
Cell Movement - physiology
Cells, Cultured
Enzyme Activation - physiology
ErbB Receptors - metabolism
Extracellular Signal-Regulated MAP Kinases - metabolism
Hemostatics - pharmacology
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Matrix Metalloproteinase 9 - metabolism
Medical sciences
Mice
Mice, Knockout
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - enzymology
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - enzymology
NADH, NADPH Oxidoreductases - genetics
NADH, NADPH Oxidoreductases - metabolism
NADPH Oxidase 1
Original
Reactive Oxygen Species - metabolism
src-Family Kinases - metabolism
Thrombin - pharmacology
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Summary:Aims In atherosclerosis and restenosis, vascular smooth muscle cells (SMCs) migrate into the subendothelial space and proliferate, contributing to neointimal formation. The goal of this study was to define the signalling pathway by which Nox1 NAPDH oxidase mediates SMC migration. Methods and results SMCs were cultured from thoracic aorta from Nox1−/y (Nox1 knockout, KO) and wild-type (WT) mice. In response to thrombin, WT but not Nox1 KO SMCs generated increased levels of reactive oxygen species (ROS). Deficiency of Nox1 prevented thrombin-induced phosphorylation of Src and the subsequent transactivation of the epidermal growth factor receptor (EGFR) at multiple tyrosine residues. Next, activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and matrix metalloproteinase-9 (MMP-9) by thrombin was inhibited by the EGFR inhibitor AG1478 and in Nox1 KO SMCs. Thrombin-induced shedding of N-cadherin from the plasma membrane was dependent on the presence of Nox1 and was blocked by AG1478 and an inhibitor of metalloproteinases. Migration of SMCs to thrombin was impaired in the Nox1 KO SMCs and was restored by expression of Nox1. Finally, treatment of WT SMCs with AG1478 abrogated Nox1-dependent SMC migration. Conclusions The Nox1 NADPH oxidase signals through EGFR to activate MMP-9 and promote the shedding of N-cadherin, thereby contributing to SMC migration.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvr308