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- Title
Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1.
- Authors
Ali, Ziad A.; de Jesus Perez, Vinicio; Ke Yuan; Orcholski, Mark; Pan, Stephen; Wei Qi; Chopra, Caurav; Adams, Christopher; Yoko Kojima; Leeper, Nicholas J.; Xiumei Çu; Zaleta-Rivera, Kathia; Kimihiko Kato; Yoshiji Yamada; Mitsutoshi Oguri; Kuchinsky, Allan; Hazen, Stanley L.; Jukema, J. Wouter; Ganesh, Santhi K.; Nabel, Elizabeth C.
- 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 (GPX7) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Cpx7 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 GPX7 with the orphan protooncogene receptor tyrosine kinase ROST. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS7 variant with pathological remodeling. Decreased CPX1 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 CPX7 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 GPXI-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote R0S1 activation and mediate vascular remodeling.
- Subjects
PROTEIN-tyrosine kinases; ATHEROSCLEROSIS; ANGIOPLASTY; GLUTATHIONE peroxidase genetics; PROTO-oncogenes; STENOSIS
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 12, p5159
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI77484