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Published on: September 14, 2021

Peroxisome proliferator-activated receptor gamma inhibits transforming growth factor beta-induced connective tissue

M Fu1, J Zhang, X Zhu

  • 1Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, USA.

The Journal of Biological Chemistry
|October 9, 2001
PubMed

Insights

Activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibits vascular smooth muscle cell growth. PPAR gamma activation suppresses connective tissue growth factor (CTGF) production by interfering with the Smad3 signaling pathway.

Area of Science:

  • Vascular biology
  • Molecular medicine
  • Cell signaling

Background:

  • Peroxisome proliferator-activated receptor gamma (PPAR gamma) activation inhibits vascular smooth muscle cell (VSMC) proliferation and neointima formation after balloon injury.
  • The precise mechanisms underlying PPAR gamma's inhibitory effects on VSMC growth and matrix production remain unclear.
  • Connective tissue growth factor (CTGF) is a critical regulator of extracellular matrix production, and its regulation by PPAR gamma may be key to inhibiting neointima formation.

Purpose of the Study:

  • To investigate the mechanisms by which PPAR gamma activation attenuates VSMC growth and matrix production.
  • To determine if PPAR gamma activation inhibits transforming growth factor beta (TGF-beta)-induced CTGF production.
  • To elucidate the molecular pathways involved in PPAR gamma's regulation of CTGF expression.

Main Methods:

  • Human aortic smooth muscle cells (HASMCs) were treated with PPAR gamma ligands (15-deoxyprostaglandin J(2), GW7845) and TGF-beta.
  • CTGF production and mRNA expression were measured, along with the effects of PPAR gamma antagonist (GW9662).
  • CTGF promoter activity was assessed using a cloned promoter construct, and interactions with Smad3/Smad4 were studied via glutathione S-transferase pull-down assays.

Main Results:

  • PPAR gamma ligands significantly inhibited TGF-beta-induced CTGF production and mRNA expression in HASMCs in a dose-dependent manner.
  • The inhibitory effect of PPAR gamma on CTGF expression was dependent on PPAR gamma activation, as shown by the antagonist GW9662.
  • PPAR gamma activation suppressed TGF-beta-induced CTGF promoter activity, an effect rescued by Smad3 overexpression but not Smad4.
  • PPAR gamma was found to physically interact with Smad3, but not Smad4.

Conclusions:

  • PPAR gamma activation inhibits TGF-beta-induced CTGF expression in HASMCs.
  • This inhibition is mediated by PPAR gamma directly interfering with the Smad3 signaling pathway.
  • These findings reveal a novel mechanism by which PPAR gamma agonists may prevent neointima formation after vascular injury.

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