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

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 A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the 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 duanyu16701 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving duanyu16701 activity via s-glutathiolation of critical residues of the duanyu16701 tyrosine phosphatase SHP-2. duanyu16701 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 duanyu16701 activation and mediate vascular remodeling.

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