Simvastatin reduces lipoprotein-associated phospholipase A2 in lipopolysaccharide-stimulated human monocyte-derived macrophages through inhibition of the mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 mitogen-activated protein kinase pathway.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), which is produced primarily by macrophages and is predominately found in the blood and in atherosclerotic plaques, represents a potentially promising target for combating atherosclerosis. Although statins are known to decrease the levels and activity of circulating and plaque Lp-PLA(2) during atherosclerosis, little is known regarding the mechanisms underlying inhibition of Lp-PLA(2) by statins. Therefore, the aim of this study was to explore the molecular mechanisms responsible for inhibition of Lp-PLA(2) by statins. Our results showed that treatment with simvastatin inhibited lipopolysaccharide (LPS)-induced increases in Lp-PLA(2) expression and secreted activity in human monocyte–derived macrophages in a dose- and time-dependent manner. These effects could be reversed by treatment with mevalonate or geranylgeranyl pyrophosphate (GGPP), but not by treatment with squalene or farnesyl pyrophosphate. Treatment with the Rho inhibitor C3 exoenzyme also inhibited LPS-induced increases in Lp-PLA(2) expression and secreted activity, mimicking the effects of simvastatin. In addition, treatment with simvastatin blocked LPS-induced activation of RhoA, which could be abolished by treatment with GGPP. Inhibition of p38 mitogen-activated protein kinase (MAPK), but not extracellular signal regulated kinase 1/2 or Jun N-terminal kinase, suppressed LPS-induced increases in Lp-PLA(2) expression and secreted activity, similar to the effects of simvastatin. Treatment of human monocyte–derived macrophages with either simvastatin or C3 exoenzyme prevented LPS-induced activation of p38 MAPK, which could be abolished by treatment with GGPP. Together, these results suggest that simvastatin reduces Lp-PLA(2) expression and secreted activity in LPS-stimulated human monocyte–derived macrophages through the inhibition of the mevalonate–GGPP–RhoA-p38 MAPK pathway. These observations provide novel evidence that statins have pleiotropic effects and suggest that inhibition of Lp-PLA(2) via this mechanism may account, at least in part, for the clinical benefit of statins in combating atherosclerosis.
Department of Cardiology, Peking University People’s Hospital, No. 11 Xizhimen South St, Xicheng District, Beijing 100044, China.
Jun-Xian
JX
Song
Jing-Yi
JY
Ren
Hong
H
Chen
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008070:Lipopolysaccharides; D011106:Polyisoprenyl Phosphates; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid