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Intimal smooth muscle cells as a target for peroxisome proliferator-activated receptor-gamma ligand therapy

David Bishop-Bailey1, Timothy Hla, Timothy D Warner

  • 1Department of Cardiac, Vascular, and Inflammation Research, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK. d.bishop-bailey@qmul.ac.uk

Circulation Research
|August 10, 2002
PubMed

Insights

Peroxisome proliferator-activated receptor gamma (PPARgamma) activation limits vascular pathologies. Intimal smooth muscle cells, crucial in vascular disease, show higher functional PPARgamma, making them a key target for antiatherosclerotic therapies.

Area of Science:

  • Vascular Biology
  • Molecular Medicine
  • Pharmacology

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARgamma) activation is a novel target for mitigating vascular pathologies.
  • PPARgamma is notably expressed in the neointimal microenvironment of vascular disease models.
  • Intimal smooth muscle cells (SMCs) exhibit higher functional PPARgamma levels compared to medial SMCs.

Purpose of the Study:

  • To investigate the functional differences in PPARgamma activity between intimal and medial SMCs.
  • To explore the effects of PPARgamma ligands on intimal versus medial SMCs.
  • To determine the role of cyclooxygenase (COX) in endogenous PPARgamma ligand production.

Main Methods:

  • In vitro studies comparing intimal and medial SMCs.
  • Treatment with PPARgamma ligand rosiglitazone to assess CD36 expression and apoptosis.
  • Measurement of cyclooxygenase-2 (COX-2) protein and eicosanoid release.
  • PPAR reporter gene assays with and without COX inhibitors and arachidonic acid stimulation.

Main Results:

  • Intimal SMCs demonstrated higher functional PPARgamma than medial SMCs.
  • Rosiglitazone induced CD36 expression and apoptosis more potently in intimal SMCs.
  • Intimal SMCs showed higher COX-2 levels and produced more eicosanoids.
  • Arachidonic acid stimulation activated PPAR reporter genes in a COX-inhibitor-sensitive manner, correlating with increased CD36.

Conclusions:

  • Intimal SMCs possess functionally higher PPARgamma levels, representing a critical target for therapeutic intervention.
  • PPARgamma ligands exhibit differential potency for targets like CD36 and apoptosis induction in intimal SMCs.
  • Cyclooxygenase activity can generate endogenous PPARgamma ligands, highlighting an autocrine/paracrine signaling pathway in vascular smooth muscle cells.

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