Protein kinase N1 is a novel substrate of NFATc1-mediated cyclin D1-CDK6 activity and modulates vascular smooth muscle cell division and migration leading to inward blood vessel wall remodeling

J Biol Chem. 2012 Oct 19;287(43):36291-304. doi: 10.1074/jbc.M112.361220. Epub 2012 Aug 13.

Abstract

Toward understanding the mechanisms of vascular wall remodeling, here we have studied the role of NFATc1 in MCP-1-induced human aortic smooth muscle cell (HASMC) growth and migration and injury-induced rat aortic wall remodeling. We have identified PKN1 as a novel downstream target of NFATc1-cyclin D1/CDK6 activity in mediating vascular wall remodeling following injury. MCP-1, a potent chemoattractant protein, besides enhancing HASMC motility, also induced its growth, and these effects require NFATc1-dependent cyclin D1 expression and CDK4/6 activity. In addition, MCP-1 induced PKN1 activation in a sustained and NFATc1-cyclin D1/CDK6-dependent manner. Furthermore, PKN1 activation is required for MCP-1-induced HASMC growth and migration. Balloon injury induced PKN1 activation in NFAT-dependent manner and pharmacological or dominant negative mutant-mediated blockade of PKN1 function or siRNA-mediated down-regulation of its levels substantially suppressed balloon injury-induced smooth muscle cell migration and proliferation resulting in reduced neointima formation. These novel findings suggest that PKN1 plays a critical role in vascular wall remodeling, and therefore, it could be a promising new target for the next generation of drugs for vascular diseases, particularly restenosis following angioplasty, stent implantation, or vein grafting.

Publication types

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

MeSH terms

  • Animals
  • Cell Division*
  • Cell Movement*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / metabolism*
  • Enzyme Activation
  • Graft Occlusion, Vascular / genetics
  • Graft Occlusion, Vascular / metabolism
  • Graft Occlusion, Vascular / pathology
  • Humans
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Mutation
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Neointima / genetics
  • Neointima / metabolism
  • Neointima / pathology
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Rats

Substances

  • CCND1 protein, human
  • Ccnd1 protein, rat
  • NFATC Transcription Factors
  • NFATC1 protein, human
  • Cyclin D1
  • protein kinase N
  • Protein Kinase C
  • CDK6 protein, human
  • Cdk6 protein, rat
  • Cyclin-Dependent Kinase 6