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PPAR Research
Volume 2009, Article ID 438673, 10 pages
Research Article

A Dominant-Negative PPAR Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells

1The Methodist Hospital Research Institute, Houston, TX 77030, USA
2Takeda America Holdings, Deerfield, IL 60015, USA

Received 3 September 2009; Accepted 24 November 2009

Academic Editor: Tianxin Yang

Copyright © 2009 Joey Z. Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


PPAR ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPAR mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPAR promoted G1 S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPAR expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPAR inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPAR expression, however, did not up-regulate positive cell cycle regulators in PPAR -deficient cells, strongly suggesting that DN-PPAR effects on cell cycle result from blocking the function of endogenous wild-type PPAR . DN-PPAR expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPAR -induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPAR promotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs).