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.
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.
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Nikhlesh K
NK
Singh
Venkatesh
V
Kundumani-Sridharan
Sanjay
S
Kumar
Shailendra K
SK
Verma
Sivareddy
S
Kotla
Hideyuki
H
Mukai
Mark R
MR
Heckle
Gadiparthi N
GN
Rao
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006083:Graft Occlusion, Vascular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058426:Neointima / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats
C530104:CCND1 protein, human; C530106:Ccnd1 protein, rat; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D019938:Cyclin D1; C061570:protein kinase N; D011493:Protein Kinase C; C495911:CDK6 protein, human; C495913:Cdk6 protein, rat; D051361:Cyclin-Dependent Kinase 6