Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1
Ziad A. Ali, … , Thomas Quertermous, Euan A. Ashley
Ziad A. Ali, … , Thomas Quertermous, Euan A. Ashley
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5159-5174. https://doi.org/10.1172/JCI77484.
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Research Article

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

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.

Authors

Ziad A. Ali, Vinicio de Jesus Perez, Ke Yuan, Mark Orcholski, Stephen Pan, Wei Qi, Gaurav Chopra, Christopher Adams, Yoko Kojima, Nicholas J. Leeper, Xiumei Qu, Kathia Zaleta-Rivera, Kimihiko Kato, Yoshiji Yamada, Mitsutoshi Oguri, Allan Kuchinsky, Stanley L. Hazen, J. Wouter Jukema, Santhi K. Ganesh, Elizabeth G. Nabel, Keith Channon, Martin B. Leon, Alain Charest, Thomas Quertermous, Euan A. Ashley

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Figure 1

Increased atherosclerosis and in-stent neointima in Gpx1–/– Apoe–/– mice.

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Increased atherosclerosis and in-stent neointima in Gpx1–/– Apoe–/– mice...
(A) Transcriptional profiling of human coronary atherectomy specimens of control (AHA class I lesions), atherosclerosis (AHA class III–V lesions), or in-stent stenosis identified that GPX1 expression was incrementally lower in atherosclerosis and in-stent stenosis. *P < 0.01 vs. control; #P < 0.05 vs. atherosclerosis. n = 55 atherosclerosis/34 in-stent stenosis. (B) Relative area of atherosclerosis in the aortic root and lesion burden in aorta were increased in Gpx1–/– Apoe–/– mice compared with Gpx1+/+ Apoe–/– mice (*P < 0.02, n = 8–15/group). Black scale bar: 50 μm. White scale bar: 0.5 mm. (C) mRNA levels of Gpx1 in Gpx1+/+ Apoe–/– mice were lower in aorta that had undergone BAS compared with uninjured aorta harvested at 28 days. *P = 0.05. n = 4/group. (D) Gpx1–/– Apoe–/– mice 4 weeks following BAS developed significantly greater neointimal hyperplasia compared with control Gpx1+/+ Apoe–/–. *P < 0.05. Although overall neointimal cell density was higher in Gpx1–/– Apoe–/– mice, there was no difference in cell density when expressed per unit area between groups. Scale bar: 50 μm. Black arrowheads denote neointima.