Cyclin D1 is a bona fide target gene of NFATc1 and is sufficient in the mediation of injury-induced vascular wall remodeling.
Platelet-derived growth factor BB induced cyclin D1 expression in a time- and nuclear factor of activated T cells (NFAT)-dependent manner in human aortic smooth muscle cells (HASMCs), and blockade of NFATs prevented HASMC DNA synthesis and their cell cycle progression from G(1) to S phase. Selective inhibition of NFATc1 by its small interfering RNA also blocked HASMC proliferation and migration. Characterization of the cyclin D1 promoter revealed the presence of several NFAT binding sites, and the site at nucleotide -1333 was found to be sufficient in mediating platelet-derived growth factor BB-induced cyclin D1 promoter-luciferase reporter gene activity. In addition to its role in cell cycle progression, cyclin D1 mediated HASMC migration in an NFATc1-dependent manner. Balloon injury-induced cyclin D1-CDK4 activity requires NFAT activation, and adenovirus-mediated transduction of cyclin D1 was found to be sufficient to overcome the blockade effect of NFATs by VIVIT on balloon injury-induced vascular wall remodeling events, including smooth muscle cell migration from the medial to luminal region, their proliferation in the intimal region, and neointima formation. Together, these results provide more mechanistic evidence for the role of NFATs, particularly NFATc1, in the regulation of HASMC proliferation and migration as well as vascular wall remodeling. NFATc1 could be a potential therapeutic target against the renarrowing of artery after angioplasty.
Karpurapu
Manjula
M
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Wang
Dong
D
Van Quyen
Dong
D
Kim
Tae-Kang
TK
Kundumani-Sridharan
Venkatesh
V
Pulusani
Srinidhi
S
Rao
Gadiparthi N
GN
D017130:Angioplasty / Q000009:adverse effects; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D002339:Carotid Arteries / Q000473:pathology; D020212:Carotid Artery Injuries / Q000378:metabolism; D002453:Cell Cycle; D002465:Cell Movement; D002469:Cell Separation; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D005434:Flow Cytometry; D006801:Humans; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D050778:NFATC Transcription Factors / Q000378:metabolism*
D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4