Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) by atorvastatin is mediated by 15-deoxy-delta-12,14-PGJ(2)

作者：Ye Yumei; Nishi Shawn P; Manickavasagam Saraswathy; Lin Yu; Huang Ming He; Perez Polo J Regino; Uretskya Barry F; Birnbaum Yochai^*

来源：Prostaglandins & Other Lipid Mediators, 2007, 84(1-2): 43-53.

DOI：10.1016/j.prostaglandins.2007.04.001

• PPAR-gamma
• 15-deoxy-delta-I 2,14-PGJ(2)
• atorvastatin
• pioglitazone
• cyclooxygenase-2
• PGD2
• synthase

Several studies suggested that 3-hydroxy-3-methylglutai-yi coenzyme A (HMG-CoA) reductase inhibitors (statins) activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Atorvastatin (ATV) increases myocardial levels of prostaglandins (PG) by upregulating and activating cytosolic-phospholipase-A, and cycloxygenase-2 (COX2). We investigated whether ATV activates PPAR-gamma via 15-deoxy-delta-12,14-PGJ(2) (15DPGJ(2)) an endogenous ligand of PPAR-gamma and a product of PGD(2), and to compare the effects of pioglitazone (PIO), a known direct PPAR-gamma activator, to that of ATV. First we measured myocardial 15DPGJ2 levels in the rat heart after a 3-day pretreatment with oral ATV (10 mg/(kg d)), PIO (10 mg/(kg d)), ATV + PIO, ATV + COX1 inhibitor, and ATV + COX2 inhibitor. We also assessed in human umbilical venous endothelial cells (HUVEC) whether ATV and PIO activate PPAR-gamma via 15DPGJ(2), using siRNA targeted to PGD2 synthase. Both 15DPGJ2 levels and PPAR-gamma activation were assessed. ATV and PIO increased myocardial 15DPGJ2 levels in the rat myocardium and HUVEC. siRNA inhibited this increase in both groups. Both ATV and PIO augmented PPAR-gamma activation while co-treatment with siRNA completely blocked the ATV effect but only partially inhibited the PIO effect. In conclusion, both ATV and PIO activate PPAR-gamma and increase myocardial 15DPGJ(2) levels. Activation of PPAR-gamma by ATV is mediated solely by 15DPGJ(2), whereas PIO activates PPAR-gamma both directly and indirectly via 15DPGJ(2).

• 出版日期2007-8