Induction of microRNA-221 by platelet-derived growth factor signaling is critical for modulation of vascular smooth muscle phenotype

J Biol Chem. 2009 Feb 6;284(6):3728-38. doi: 10.1074/jbc.M808788200. Epub 2008 Dec 15.

Abstract

The platelet-derived growth factor (PDGF) signaling pathway is a critical regulator of animal development and homeostasis. Activation of the PDGF pathway leads to neointimal proliferative responses to artery injury; it promotes a switch of vascular smooth muscle cells (vSMC) to a less contractile phenotype by inhibiting the SMC-specific gene expression and increasing the rate of proliferation and migration. The molecular mechanism for these pleiotropic effects of PDGFs has not been fully described. Here, we identify the microRNA-221 (miR-221), a small noncoding RNA, as a modulator of the phenotypic change of vSMCs in response to PDGF signaling. We demonstrate that miR-221 is transcriptionally induced upon PDGF treatment in primary vSMCs, leading to down-regulation of the targets c-Kit and p27Kip1. Down-regulation of p27Kip1 by miR-221 is critical for PDGF-mediated induction of cell proliferation. Additionally, decreased c-Kit causes inhibition of SMC-specific contractile gene transcription by reducing the expression of Myocardin (Myocd), a potent SMC-specific nuclear coactivator. Our study demonstrates that PDGF signaling, by modulating the expression of miR-221, regulates two critical determinants of the vSMC phenotype; they are SMC gene expression and cell proliferation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arteries / injuries
  • Arteries / metabolism
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p27
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / metabolism*
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Platelet-Derived Growth Factor / pharmacology*
  • Proto-Oncogene Proteins c-kit / biosynthesis
  • Proto-Oncogene Proteins c-kit / genetics
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Trans-Activators / biosynthesis
  • Trans-Activators / genetics

Substances

  • CDKN1B protein, human
  • Intracellular Signaling Peptides and Proteins
  • MIRN221 microRNA, human
  • MicroRNAs
  • Nuclear Proteins
  • Platelet-Derived Growth Factor
  • Trans-Activators
  • myocardin
  • Cyclin-Dependent Kinase Inhibitor p27
  • Proto-Oncogene Proteins c-kit