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

Abstract

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