title: Protein kinase C-eta and phospholipase D2 pathway regulates foam cell formation via regulator of G protein signaling 2.
abstract: Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for Galpha(q), which is involved in regulating various vascular functions. To understand how RGS2 regulates foam cell formation, the present study identified signaling pathways controlled by lipopolysaccharide (LPS) and discovered new mechanisms whereby protein kinase C (PKC)-eta and phospholipase D (PLD) 2 regulate RGS2 expression. The toll-like receptor (TLR) 4 agonist LPS caused foam cell formation of Raw264.7 macrophages and dramatically decreased RGS2 mRNA expression. RGS2 down-regulation by LPS was partially recovered by TLR4 small interfering RNA (siRNA). Peritoneal macrophages were separated from wild-type and TLR4 mutant mice, and treatment with LPS showed RGS2 expression decrease in wild-type macrophages but no change in TLR4 mutant macrophages. RGS2 overexpression was suppressed, whereas RGS2 down-regulation accelerated foam cell formation by LPS. Treatment of PKC-eta pseudosubstrate weakened foam cell formation and recovered RGS2 down-regulation by LPS. In addition, LPS or phorbol 12-myristate 13-acetate stimulated PLD activity, and the pretreatment of PLD inhibitor weakened foam cell formation and recovered RGS2 down-regulation. Inhibition of PLD2 expression by siRNA also weakened foam cell formation and partially recovered LPS-mediated RGS2 down-regulation. On the other hand, PLD2 overexpression intensified RGS2 down-regulation and foam cell formation by LPS. These results suggest that LPS causes foam cell formation by increasing PKC-eta and PLD2 activity by down-regulating RGS2 expression via TLR4 dependently.
authors.affiliation: Aging-Associated Vascular Disease Research Center, Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, Daegu, South Korea.
authors.forename: Hyung-Kyoung
authors.initials: HK
authors.lastname: Lee
authors.forename: Seungeun
authors.initials: S
authors.lastname: Yeo
authors.forename: Jin-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Jin-Gu
authors.initials: JG
authors.lastname: Lee
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
authors.forename: Chuhee
authors.initials: C
authors.lastname: Lee
authors.forename: Suk-Hwan
authors.initials: SH
authors.lastname: Baek
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005487:Foam Cells / Q000276:immunology* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010739:Phospholipase D / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C; D020710:RGS Proteins; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D008070:Lipopolysaccharides; D020710:RGS Proteins; C087182:RGS2 protein, human; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C081975:protein kinase C eta; D011493:Protein Kinase C; C105606:phospholipase D2; D010739:Phospholipase D; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate