Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells

Abstract

Changes in plasma lipoprotein profiles, especially low levels of high-density lipoprotein (HDL), are a common biomarker for several inflammatory and immune diseases, including atherosclerosis and rheumatoid arthritis. We examined the effect of simvastatin on HDL-induced anti-inflammatory actions. HDL and sphingosine 1-phosphate (S1P), a bioactive lipid component of the lipoprotein, inhibited TNF α-induced expression of VCAM-1, which was associated with NO synthase (NOS) activation, in human umbilical venous endothelial cells. The HDL- but not S1P-induced anti-inflammatory actions were enhanced by a prior treatment of the cells with simvastatin in a manner sensitive to mevalonic acid. Simvastatin stimulated the expression of scavenger receptor class B type I (SR-BI) and endothelial NOS. As for S1P receptors, however, the statin inhibited the expression of S1P3 receptor mRNA but caused no detectable change in S1P1 receptor expression. The reconstituted HDL, a stimulator of SR-BI, mimicked HDL actions in a simvastatin-sensitive manner. The HDL- and reconstituted HDL-induced actions were blocked by small interfering RNA specific to SR-BI regardless of simvastatin treatment. The statin-induced expression of SR-BI was attenuated by constitutively active RhoA and small interfering RNA specific to peroxisome proliferator-activated receptor-α. Administration of simvastatin in vivo stimulated endothelial SR-BI expression, which was accompanied by the inhibition of the ex vivo monocyte adhesion in aortas from TNF α-injected mice. In conclusion, simvastatin induces endothelial SR-BI expression through a RhoA- and peroxisome proliferator-activated receptor-α-dependent mechanism, thereby enhancing the HDL-induced activation of NOS and the inhibition of adhesion molecule expression.

Mechanism and Role of High Density Lipoprotein-induced Activation of AMP-activated Protein Kinase in Endothelial Cells

“…The S1P content in the rHDL and cholesterol-loaded rHDL was undetectable by our S1P assay method (22). The sources of all other reagents were described previously (19,23,24). Unless otherwise stated, S1P (1 M), rHDL (500 g protein/ml), and native HDL (500 g protein/ ml) were used in this study.…”

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

“…HDL is reported to inhibit VCAM-1 expression in endothelial cells (4) in an SR-B1-specific manner (44). We hypothesized that MPO-dependent oxidative modification of HDL may inhibit this antiinflammatory and atheroprotective activity of HDL.…”

Effects of Established Hypolipidemic Drugs on HDL Concentration, Subclass Distribution, and Function

“…In vitro experiments have indeed shown that statin-mediated improvement of endothelial function is due to a direct effect of the drug on endothelial cells. Incubation of endothelial cells with different statins promotes a significant increase expression of SR-BI and S1P receptors and of eNOS, with a consequent increased production of NO after incubation with HDL (Igarashi et al 2007;Kimura et al 2008). A recent study performed on subjects with isolated low HDL-C showed that FMD was significantly improved after 4 weeks treatment with pravastatin, and multiple regression analysis revealed that changes in HDL-C and EPC number were independent predictors of FMD increase (Higashi et al 2010).…”