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COPS5\/CSN5\/JAB1 harbours the deneddylase of the COP9 signalosome (CSN) holocomplex but also has deneddylation-independent function. The role of COPS5 in VSMCs remains obscure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>COPS5\/CSN5 was increased in human idiopathic pulmonary hypertension neointima and atherosclerotic lesions and rabbit vein grafts. Smooth muscle\u2013restricted COPS5 knockout (COPS5-SMKO) markedly inhibited left common carotid artery ligation\u2013induced VSMC dedifferentiation, proliferation, and NH in mice. However, COPS8 hypomorphism (COPS8-hypo) exhibiting increased COPS5\/CSN5 mini-complexes and enhanced nuclear export of TP53\/p53 and CDKN1B\/p27 displayed significantly exacerbated NH and VSMC dedifferentiation and proliferation in vivo and in cellulo. Inhibiting COPS5 nuclear export either pharmacologically or genetically suppressed the enhanced dedifferentiation and hyperproliferation and restored nuclear TP53\/p53 and CDKN1B\/p27 in COPS8 hypomorphic VSMCs. Interestingly, inhibition of COPS5 deneddylase activity had no such effect on VSMC phenotypic modulation but significantly suppressed proliferation, highlighting distinct roles of COPS5 nuclear export and deneddylase functions. Moreover, overexpressing wild-type COPS5 selectively increased COPS5\/CSN5 mini-complexes, further promoted nuclear export of TP53\/p53 and PDGF-BB induced increases in nuclear KLF4 and VSMC dedifferentiation and proliferation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Vessel injury up-regulates vascular COPS5\/CSN5. Nuclear export driven by the increased COPS5\/CSN5 mini-complexes in VSMCs mediates and promotes VSMC dedifferentiation and phenotypic modulation, whereas the CSN deneddylase activity is not required for VSMC dedifferentiation but is crucial for VSMC proliferation during NH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag067","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:45:14Z","timestamp":1773924314000},"page":"778-795","source":"Crossref","is-referenced-by-count":2,"title":["Nuclear export by COPS5\/CSN5\/JAB1 mediates vascular smooth muscle cell dedifferentiation in neointimal hyperplasia"],"prefix":"10.1093","volume":"122","author":[{"given":"Samiksha","family":"Giri","sequence":"first","affiliation":[{"name":"Division of Biomedical and Translational Sciences, University of South Dakota Sanford School of Medicine , Vermillion, SD 57069 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