Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

J Clin Invest. 2014 Dec;124(12):5159-74. doi: 10.1172/JCI77484. Epub 2014 Nov 17.

Abstract

Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Crizotinib
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Glutathione Peroxidase / biosynthesis
  • Glutathione Peroxidase / genetics
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Mutation, Missense
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Vascular Remodeling*

Substances

  • Muscle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Protein-Tyrosine Kinases
  • ROS1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Ros1 protein, mouse