Intimal Smooth Muscle Cells as a Target for Peroxisome Proliferator-Activated Receptor-&ggr; Ligand Therapy

Abstract— Activation of the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;), is a newly defined target for limiting vascular pathologies. PPAR&ggr; 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&ggr; than medial smooth muscle cells. The PPAR&ggr; 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&ggr;, PPAR&ggr; 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&ggr; ligands.