Statins Modulate Cyclooxygenase‐2 and Microsomal Prostaglandin E Synthase‐1 in Human Hepatic Myofibroblasts

Abstract

Statins have been shown to exert anti-inflammatory and anti-fibrogenic properties in the liver. In the present study, we explored the mechanisms underlying anti-fibrogenic effects of statins in isolated hepatic myofibroblasts and focused on cyclooxyegnase-2, a major anti-proliferative pathway in these cells. We show that simvastatin and fluvastatin inhibit thymidine incorporation in hMF in a dose-dependent manner. Pretreatment of cells with NS398, a COX-2 inhibitor, partially blunted this effect. cAMP levels, essential to the inhibition of hMF proliferation, were increased by statins and inhibited by non-steroidal anti-inflammatory drugs. Since statins modify prenylation of some important proteins in gene expression, we investigated the targets involved using selective inhibitors of prenyltransferases. Inhibition of geranylgeranylation resulted in the induction of COX-2 and mPGES-1. Using gel retardation assays, we further demonstrated that statins potentially activated the NFκB and CRE/E-box binding for COX-2 promoter and the binding of GC-rich regions and GATA for mPGES-1. Together these data demonstrate that statin limit hepatic myofibroblasts proliferation via a COX-2 and mPGES-1 dependent pathway. These data suggest that statin-dependent increase of prostaglandin in hMF contributes to its anti-fibrogenic effect.

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

“…In vitro, simvastatin strongly impaired endothelial cell function, most likely by inducing endothelial cell death. Although our findings strongly contradict the notion that simvastatin protects and augments endothelial cell function (42) , our findings agree with those of scattered reports of simvastatin exerting a proinflammatory rather than anti-inflammatory effects compared to other, primarily water soluble statins 43 , 44 ; simvastatin inducing maladaptive changes in endothelial cells and other cell types 45 , 46 ; and simvastatin inducing rather than reducing COX2 expression (47) . An increased expression of COX2 induced by simvastatin may have potentially contributed not only to pulmonary complications following CA/CPR but also to ischemic brain injury following asphyxial CA 48 , 49 .…”

Effects of Statins and Xuezhikang on the Expression of Secretory Phospholipase A2, Group IIA in Rat Vascular Smooth Muscle Cells

“…There is ample evidence showing that two NF-κB binding elements (_214/_223and _380/_388bp) are activated by statins in human monocytes, aortic smooth muscle cells, and human hepatocyte cells. 63) Moreover, Menschikowski, et al demonstrated that statins may stimulate the expression of sPLA2-IIA synergistically with IFN-γ by the NF-κB signaling pathway. 29) Therefore, similar to our results, we believe the NF-κB signaling pathway also responsible for the synergistic effects of IL -1β and statins, which lead to the dramatic expression of sP-LA2-IIA in VMSCs.…”

Effects of Statins on Renin–Angiotensin System

“…Statins regulate renin secretion by affecting these cAMP activators. For example, in some studies, it has been shown that statins can induce prostaglandin I2 and E2 production by inhibiting geranylgeranylation, the process of attaching geranylgeranyl diphosphate to cysteine residues at the C-terminus of specific proteins, and inducing mRNA expression of COX-2, which metabolizes arachidonic acid into prostaglandins [ 31 , 32 , 33 ]. Induction of COX-2 expression by statins is driven by sterol-dependent and ERK1/2- and p38 MAPK-dependent pathways [ 34 ].…”