Capital Institute of Pediatrics, Beijing 100020, China.
Institute of Molecular Medicine, Peking University, Beijing 100871, China.
Nat Commun. 2017 Aug 11;8:16016. doi: 10.1038/ncomms16016.
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.
虽然血管平滑肌细胞（VSMC）增殖是所有心血管过度增生性疾病的基础，但我们对导致这种细胞过程的分子机制的理解仍不完整。在这里，我们报告 SRSF1（丝氨酸/精氨酸丰富的剪接因子 1），一种必需的剪接因子，促进 VSMC 增殖和损伤诱导的新生内膜形成。体内血管损伤和体外增殖刺激刺激 SRSF1 的表达。在 SMC 中特异性缺乏 SRSF1 的小鼠在钢丝损伤后内膜增厚减少。在大鼠动脉中表达 SRSF1 可增强新内膜形成。SRSF1 的过表达增加，而 SRSF1 的敲低则抑制培养的人主动脉和冠状动脉平滑肌细胞的增殖和迁移。在机制上，SRSF1 有利于诱导截短的 p53 异构体 Δ133p53，其具有同等的增殖作用，并通过 Δ133p53-EGR1 复合物反过来转录激活 Krüppel 样因子 5（KLF5），导致细胞周期进程加速和 VSMC 增殖增加。我们的研究为血管过度增生性疾病提供了一个潜在的治疗靶点。
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