Published online before print July 11, 2002, doi: 10.1161/01.RES.0000029080.15742.85
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Submitted on January 24, 2002
Revised on June 25, 2002
Accepted on June 26, 2002
Intimal Smooth Muscle Cells as a Target for Peroxisome Proliferator-Activated Receptor-
Ligand Therapy
David Bishop-Bailey *;
From the Department of Cardiac, Vascular, and Inflammation Research (D.B.-B., T.D.W.), William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK; and the Center for Vascular Biology, Department of Physiology (T.H.), University of Connecticut Health Center, Farmington, Conn.
* To whom correspondence should be addressed. E-mail: d.bishop-bailey{at}qmul.ac.uk.
Activation of the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor (PPAR), is a newly defined target for limiting vascular pathologies. PPAR 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 PPAR than medial smooth muscle cells. The PPAR 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 PPAR, PPAR 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 PPAR ligands.
Key words: peroxisome proliferator-activated receptor-
•
cyclooxygenase-2 •
intimal smooth muscle cells •
atherosclerosis •
restenosis
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