P88-S Macromolecular Interactions: PPARy Ligands Enhance Phagocytic Clearance of Apoptotic Macrophages

摘要

Peroxisome proliferator-activated receptor (PPAR)γ ligands decrease early atherosclerosis lesions in experimental animal models, but their effects on advanced atherosclerosis are not known. A unique process in advanced atherosclerosis is the accumulation of free cholesterol (FC) by macrophages (Mfs), which, according to previous in-vivo studies, can result in Mf death, lesional necrosis, inflammation, and plaque susceptibility to rupture. Mf apoptosis occurs through all stages of atherosclerosis, and inefficient phagocytic clearance of dying Mfs may lead to cellular necrosis and release of plaque-destabilizing factors. Here we sought to determine how PPARy agonists would affect phagocytosis of FC-induced apoptotic cells. We found that with the use of these PPARγ agonists, phagocytosis of these apoptotic cells increased significantly. This enhanced phagocytic uptake was associated with increased accumulation of filamentous actin at the interface between phagocyte and apoptotic cell, suggesting an effect of PPARy ligands on intracellular actin signaling. Indeed, macrophages treated with the PPARy ligand rosiglitazone had decreased levels of the actin-modulating protein RhoA. Thus, compounds designed to activate PPARy, inducing those in clinical use such as rosiglitazone and pioglitazone may reduce atherosclerotic maturation by enhancing phagocytic clearance of dying macrophages. Future derivations of PPARγligands may be selected to further exploit this phagocytic property.