Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) by atorvastatin is mediated by 15-deoxy-delta-12,14-PGJ2.
Several studies suggested that 3-hydroxy-3-methylglutaryl 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(2) 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 15DPGJ(2) 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 PGD(2) synthase. Both 15DPGJ(2) levels and PPAR-gamma activation were assessed. ATV and PIO increased myocardial 15DPGJ(2) 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).
Ye
Yumei
Y
The Division of Cardiology, University of Texas Medical Branch, Galveston, TX, United States.
Nishi
Shawn P
SP
Manickavasagam
Saraswathy
S
Lin
Yu
Y
Huang
Ming-He
MH
Perez-Polo
J Regino
JR
Uretsky
Barry F
BF
Birnbaum
Yochai
Y
D000818:Animals; D000069059:Atorvastatin; D018955:CD36 Antigens / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006538:Heptanoic Acids / Q000494:pharmacology*; D008954:Models, Biological; D008956:Models, Chemical; D009206:Myocardium / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018955:CD36 Antigens; D016861:Cyclooxygenase Inhibitors; D006538:Heptanoic Acids; D047495:PPAR gamma; D011758:Pyrroles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000069059:Atorvastatin; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2; D000077205:Pioglitazone