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Cyclin D1 is a bona fide target gene of NFATc1 and is sufficient in the mediation of injury‐induced vascular wall remodeling
Author(s) -
Wang Dong,
Karpurapu Manjula,
Van Quyen Dong,
KundumaniSridharan Venkatesh,
Pulusani Srinidhi,
Rao Gadiparthi N
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.603.1
Subject(s) - cyclin d1 , neointima , nfat , cancer research , microbiology and biotechnology , cyclin , cell cycle , cyclin d , platelet derived growth factor receptor , small interfering rna , cell growth , biology , chemistry , growth factor , gene , transcription factor , medicine , restenosis , receptor , biochemistry , rna , stent
Platelet‐derived growth factor BB (PDGF‐BB) induced cyclin D1 expression in a time‐ and NFAT‐dependent manner in human aortic smooth muscle cells (HASMCs) and blockade of NFATs prevented HASMC DNA synthesis and their cell cycle progression from G1 to S phase. Selective inhibition of NFATc1 by its siRNA also blocked HASMC proliferation and migration. Characterization of cyclin D1 promoter revealed the presence of several NFAT binding sites and the site at −1333 was found to be sufficient in mediating PDGF‐BB‐induced cyclin D1 promoter‐reporter gene activity. In addition to its role in cell cycle progression, cyclin D1 mediated HASMC migration in 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 SMC migration from medial to luminal region, their proliferation in the intimal region and neointima formation. Together, these results provide another 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 re‐narrowing of artery after angioplasty. This work was supported by a grant from NIH (HL069908).