SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway

Ning Xie, Min Chen, Rilei Dai, Yan Zhang, Hanqing Zhao, Zhiming Song, Lufeng Zhang, Zhenyan Li, Yuanqing Feng, Hua Gao, Li Wang, Ting Zhang, Rui-Ping Xiao, Jianxin Wu and Chun-Mei Cao ()
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Ning Xie: Capital Institute of Pediatrics
Min Chen: Capital Institute of Pediatrics
Rilei Dai: Capital Institute of Pediatrics
Yan Zhang: Institute of Molecular Medicine, Peking University
Hanqing Zhao: National Institute of Biological Sciences
Zhiming Song: Peking University, Third Hospital
Lufeng Zhang: Peking University, Third Hospital
Zhenyan Li: Capital Institute of Pediatrics
Yuanqing Feng: Institute of Molecular Medicine, Peking University
Hua Gao: Center for Bioinformatics, Peking University
Li Wang: Capital Institute of Pediatrics
Ting Zhang: Capital Institute of Pediatrics
Rui-Ping Xiao: Institute of Molecular Medicine, Peking University
Jianxin Wu: Capital Institute of Pediatrics
Chun-Mei Cao: Capital Institute of Pediatrics

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: Abstract Though vascular smooth muscle cell (VSMC) proliferation underlies all cardiovascular hyperplastic disorders, our understanding of the molecular mechanisms responsible for this cellular process is still incomplete. Here we report that SRSF1 (serine/arginine-rich splicing factor 1), an essential splicing factor, promotes VSMC proliferation and injury-induced neointima formation. Vascular injury in vivo and proliferative stimuli in vitro stimulate SRSF1 expression. Mice lacking SRSF1 specifically in SMCs develop less intimal thickening after wire injury. Expression of SRSF1 in rat arteries enhances neointima formation. SRSF1 overexpression increases, while SRSF1 knockdown suppresses the proliferation and migration of cultured human aortic and coronary arterial SMCs. Mechanistically, SRSF1 favours the induction of a truncated p53 isoform, Δ133p53, which has an equal proliferative effect and in turn transcriptionally activates Krüppel-like factor 5 (KLF5) via the Δ133p53-EGR1 complex, resulting in an accelerated cell-cycle progression and increased VSMC proliferation. Our study provides a potential therapeutic target for vascular hyperplastic disease.

Date: 2017
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DOI: 10.1038/ncomms16016

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