Peroxisome proliferator-activate inhibit development of atherosclerosis in LDL receptor-deficient mice

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and 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 demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPAR gamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPAR gamma. These findings suggest that PPAR gamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPAR gamma Ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.