TY - JOUR T1 - Protein Kinase C-η and Phospholipase D2 Pathway Regulates Foam Cell Formation via Regulator of G Protein Signaling 2 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 478 LP - 485 DO - 10.1124/mol.110.064394 VL - 78 IS - 3 AU - Hyung-Kyoung Lee AU - Seungeun Yeo AU - Jin-Sik Kim AU - Jin-Gu Lee AU - Yoe-Sik Bae AU - Chuhee Lee AU - Suk-Hwan Baek Y1 - 2010/09/01 UR - http://molpharm.aspetjournals.org/content/78/3/478.abstract N2 - Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for Gαq, 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)-η 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-η 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-η and PLD2 activity by down-regulating RGS2 expression via TLR4 dependently. ER -