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

Joey Z Liu1, Christopher J Lyon, Willa A Hsueh

  • 1The Methodist Hospital Research Institute, Houston, TX 77030, USA.

PPAR Research
|March 20, 2010
PubMed

Insights

A dominant-negative PPARgamma mutant acts as a growth factor in human coronary artery smooth muscle cells, promoting cell cycle progression and proliferation. This suggests PPARgamma plays a key role in regulating vascular smooth muscle cell growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cardiovascular Research

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands typically inhibit cell proliferation.
  • The role of PPARgamma in vascular smooth muscle cell (VSMC) growth regulation requires further elucidation.

Purpose of the Study:

  • To investigate the effect of a dominant-negative PPARgamma mutant on human coronary artery smooth muscle cell (CASMC) proliferation.
  • To elucidate the underlying molecular mechanisms, including cell cycle regulation and signaling pathways.

Main Methods:

  • Adenovirus-mediated expression of dominant-negative (DN) PPARgamma and wild-type (WT)/constitutively-active (CA) PPARgamma in CASMCs.
  • Assessment of cell cycle progression (BrdU incorporation, G1 to S phase transition).
  • Analysis of cell cycle regulatory proteins (Rb, CDC2, cyclins, MCM7) and ERK MAPKs phosphorylation.

Main Results:

  • DN-PPARgamma expression promoted G1 to S phase cell cycle progression and proliferation in CASMCs.
  • DN-PPARgamma enhanced phosphorylation of Rb, CDC2, and ERK MAPKs, and increased cyclin A, B1, D1, and MCM7 expression.
  • Overexpression of WT or CA PPARgamma inhibited cell cycle progression, while DN-PPARgamma effects were dependent on endogenous PPARgamma function.

Conclusions:

  • A dominant-negative PPARgamma mutant acts as a growth factor in CASMCs, promoting cell cycle progression.
  • DN-PPARgamma modulates cell cycle regulators and MAPK signaling pathways to drive VSMC proliferation.
  • These findings reveal a novel role for PPARgamma in controlling vascular smooth muscle cell growth.

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