Peroxisome proliferator-activate inhibit development of atherosclerosis inLDL receptor-deficient mice

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nucl ear receptor that regulates fat-cell development and glucose homeostasis an d is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPAR gamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstra ted in cultured macrophages to both positively and negatively regulate gene s implicated in the development of atherosclerosis. We report here that the PPAR gamma-specific agonists rosiglitazone and GW7845 strongly inhibited t he development of atherosclerosis in LDL receptor-deficient male mice, desp ite increased expression of the CD36 scavenger receptor in the arterial wal l. The antiatherogenic effect in male mice was correlated with improved ins ulin sensitivity and decreased tissue expression of TNF-alpha and gelatinas e B, indicating both systemic and local actions of PPAR gamma. These findin gs suggest that PPAR gamma agonists may exert antiatherogenic effects in di abetic patients and provide impetus for efforts to develop PPAR gamma Ligan ds that separate proatherogenic activities from antidiabetic and antiathero genic activities.