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Transforming growth factor-beta1 is a molecular target for the peroxisome proliferator-activated receptor delta

Hyo Jung Kim1, Sun Ah Ham, Sung Uk Kim

  • 1Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.

Circulation Research
|November 17, 2007
PubMed

Insights

Peroxisome proliferator-activated receptor (PPAR)delta activates transforming growth factor (TGF)-beta1 in vascular cells, revealing a novel anti-inflammatory pathway. This PPARdelta-TGF-beta1 axis reduces inflammatory gene expression in atherosclerosis models.

Area of Science:

  • Vascular Biology
  • Molecular Endocrinology
  • Inflammation Research

Background:

  • Peroxisome proliferator-activated receptor (PPAR)delta's role in atherogenic disorders is known, but its function in vascular smooth muscle cells (VSMCs) is unclear.
  • Understanding PPARdelta's mechanisms in VSMCs is crucial for developing treatments for vascular diseases.

Purpose of the Study:

  • To elucidate the physiological roles and functions of PPARdelta in VSMCs.
  • To investigate the molecular mechanisms underlying PPARdelta's effects on inflammatory gene expression in the vasculature.

Main Methods:

  • Investigated PPARdelta's regulation of transforming growth factor (TGF)-beta1 expression in VSMCs using activators (GW501516) and inhibitors (GW9662, siRNA).
  • Analyzed TGF-beta1 promoter activity and PPARdelta binding to response elements.
  • Examined the impact of PPARdelta activation on interleukin-1beta-induced monocyte chemoattractant protein-1 (MCP-1) expression and its mediation by TGF-beta1 and Smad3.
  • Assessed the in vivo effects of GW501516 on TGF-beta1 and MCP-1 expression in mouse thoracic aorta.

Main Results:

  • PPARdelta activation significantly upregulates TGF-beta1 expression in VSMCs via direct binding to a novel response element.
  • Ligand-activated PPARdelta suppresses interleukin-1beta-induced MCP-1 expression, a key inflammatory mediator.
  • This anti-inflammatory effect is dependent on the TGF-beta1 pathway, involving Smad3.
  • In vivo studies confirmed increased TGF-beta1 and decreased MCP-1 expression in the aorta of mice treated with a PPARdelta activator.

Conclusions:

  • Identified a novel TGF-beta1-mediated pathway through which PPARdelta exerts anti-inflammatory effects in the vasculature.
  • PPARdelta activation represents a potential therapeutic strategy for mitigating vascular inflammation and atherosclerosis.

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