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

Abstract

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