Document Type


Date of Award


Degree Name

Doctor of Philosophy (PhD)


Basic Biomedical Science

First Advisor

Xuejun Dr Wang


Neointimal hyperplasia (NH) is a common pathological response to vascular injury and mediated primarily by vascular smooth muscle cell (VSMC) migration and proliferation. The COP9 signalosome (CSN) is formed by 8 canonical subunits (CSN1 through CSN8) with its deneddylation activity residing in CSN5. Each or some of CSN subunits may have deneddylation-independent function but this is not well established. Despite the CSN being known to be a key regulator of protein degradation, its role in vascular biology remains obscure. The present study was conducted to fill these critical gaps.Our immunohistochemistry analyses revealed substantially higher CSN5 levels in the neointimal VSMCs of the pulmonary arteries of human pulmonary hypertension (PAH) than in the VSMCs of control pulmonary arteries. Left common carotid artery (LCCA) ligation induced NH and significantly increased the mRNA and protein levels of CSN subunits in the LCCA wall of adult wild type mice. Adult mice with smooth muscle cell-restricted CSN5 knockout (CSN5-SMKO) impaired cullin deneddylation and the nuclear export of p27 in vessel walls and markedly inhibited VSMC proliferation in mice. On the contrary, CSN8 hypomorphism (CSN8-hypo) significantly exacerbated NH and VSMC proliferation in vivo and in cellulo. Cytoplasmic CSN5 mini-complexes and the nuclear export of p27 were significantly increased in CSN8-hypo mouse vessels and cultured CSN8-hypo VSMCs. Nuclear export inhibition with leptomycin attenuated the PDGF-BB induced increases in VSMC proliferation in both CSN8-hypo and control VSMCs. Further, genetically disabling CSN5 nuclear export but not disabling CSN5 deneddylase activity suppressed the hyperproliferation and restored p27 nuclear localization in CSN8 hypomorphic VSMCs. Interestingly, CSN deneddylase inhibition by CSN5i-3 did not alter the hyperproliferation of cultured CSN8-hypo VSMCs but suppressed wild type VSMC proliferation in cellulo and in vivo and blocked neointimal formation in wild type mice. Thus, we have established both deneddylation by the CSN and nuclear-export by CSN5 mini-complex as the underlying mechanisms for the promotion of VSMC proliferation and NH by CSN5.

Subject Categories

Biology | Physiology


CSN5, CSN8, Neointimal hyperplasia, VSMC proliferation

Number of Pages



University of South Dakota



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