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

PPARgamma ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARgamma 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-PPARgamma promoted G1-->S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARgamma 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) PPARgamma inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARgamma expression, however, did not up-regulate positive cell cycle regulators in PPARgamma-deficient cells, strongly suggesting that DN-PPARgamma effects on cell cycle result from blocking the function of endogenous wild-type PPARgamma. DN-PPARgamma expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARgamma-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARgamma 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).