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Biochem Pharmacol. 2017 Aug 1;137:51-60. doi: 10.1016/j.bcp.2017.04.018. Epub 2017 Apr 20.

Roscovitine attenuates intimal hyperplasia via inhibiting NF-κB and STAT3 activation induced by TNF-α in vascular smooth muscle cells.

Author information

1
Institute of Chinese Integrative Medicine, Hebei Key Laboratory of Integrative Medicine on Liver-kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, PR China.
2
Department of Clinical Medical Research Center, Hebei General Hospital, Shijiazhuang, Hebei 050051, PR China.
3
Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, PR China.
4
Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, PR China; Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050091, PR China.
5
Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050091, PR China.
6
Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, PR China; Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050091, PR China. Electronic address: lay1963@126.com.
7
Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, PR China. Electronic address: jesphy@126.com.

Abstract

Roscovitine is a selective CDK inhibitor originally designed as anti-cancer agent, which has also been shown to inhibit proliferation in vascular smooth muscle cells (VSMCs). However, its effect on vascular remodeling and its mechanism of action remain unknown. In our study, we created a new intimal hyperplasia model in male Sprague-Dawley rats by trypsin digestion method, which cause to vascular injury as well as the model of rat carotid balloon angioplasty. Roscovitine administration led to a significant reduction in neointimal formation and VSMCs proliferation after injury in rats. Western blot analysis revealed that, in response to vascular injury, TNF-α stimulation induced p65 and STAT3 phosphorylation and promoted translocation of these molecules into the nucleus. p65 can physically associate with STAT3 and bind to TNF-α-regulated target promoters, such as MCP-1 and ICAM-1, to initiate gene transcription. Roscovitine can interrupt activation of NF-κB and reduce expression of TNF-α-induced proinflammatory gene, thus inhibiting intimal hyperplasia. These findings provide a novel mechanism to explain the roscovitine-mediated inhibition of intimal hyperplasia induced by proinflammatory pathways.

KEYWORDS:

Intimal hyperplasia; Phosphorylation; Roscovitine; Roscovitine (PubChem CID: 160355); STAT3; p65

PMID:
28433552
DOI:
10.1016/j.bcp.2017.04.018
[Indexed for MEDLINE]

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