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

Nat Commun. 2017 Aug 11;8:16016. doi: 10.1038/ncomms16016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Carotid Artery Injuries / pathology*
  • Carotid Artery, Common / pathology*
  • Cell Cycle
  • Cell Proliferation / genetics*
  • Cells, Cultured
  • Coronary Vessels / cytology
  • Early Growth Response Protein 1 / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Mammary Arteries
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / cytology*
  • Neointima / genetics*
  • Protein Isoforms
  • Rats
  • Serine-Arginine Splicing Factors / genetics*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Early Growth Response Protein 1
  • KLF5 protein, human
  • Klf5 protein, mouse
  • Klf5 protein, rat
  • Kruppel-Like Transcription Factors
  • Protein Isoforms
  • SRSF1 protein, human
  • Srsf1 protein, mouse
  • Tumor Suppressor Protein p53
  • Serine-Arginine Splicing Factors