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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
Abstract:
Activation of the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), is a newly defined target for limiting vascular pathologies. PPARgamma is expressed in human and animal models of vascular disease, with particularly high levels being present in the cells of the neointimal microenvironment. In the present study, we show that intimal smooth muscle cells in vitro contain higher amounts of functional PPARgamma than medial smooth muscle cells. The PPARgamma ligand rosiglitazone more potently induced CD36 expression at low concentrations, and cell death by apoptosis at higher concentrations in intimal compared with medial smooth muscle cells. Intimal smooth muscle cells also contained high levels of cyclooxygenase-2 protein, and released a more diverse and larger amount of eicosanoids on arachidonic acid stimulation. Furthermore, when exogenous arachidonic acid was added, PPAR reporter gene activation was induced in a cyclooxygenase inhibitor-sensitive manner, an effect that correlated with an increase in CD36 expression. In summary, intimal smooth muscle cells contain functionally higher levels of PPARgamma, PPARgamma ligands have high- and low-potency targets in vascular smooth muscle cells, and cyclooxygenase can serve as a source of potential endogenous PPAR ligands. Intimal vascular smooth muscle cells therefore represent a potentially important target for the antiproliferative, and antiatherosclerotic actions of PPARgamma ligands.
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.