title: 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 alpha-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 S1P(3) receptor mRNA but caused no detectable change in S1P(1) 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-alpha. 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 alpha-injected mice. In conclusion, simvastatin induces endothelial SR-BI expression through a RhoA- and peroxisome proliferator-activated receptor-alpha-dependent mechanism, thereby enhancing the HDL-induced activation of NOS and the inhibition of adhesion molecule expression.
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kimura
authors.forename: Chihiro
authors.initials: C
authors.lastname: Mogi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tomura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuwabara
authors.forename: Doon-Soon
authors.initials: DS
authors.lastname: Im
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
authors.forename: Masami
authors.initials: M
authors.lastname: Murakami
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D047493:PPAR alpha / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis* / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D047493:PPAR alpha; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D020742:rhoA GTP-Binding Protein; D013110:Sphingosine