RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP mol.110.064394 DO 10.1124/mol.110.064394 A1 Hyung-Kyoung Lee A1 Seungeun Yeo A1 Jin-Sik Kim A1 Jin-Gu Lee A1 Yoe-Sik Bae A1 Chuhee Lee A1 Suk-Hwan Baek YR 2010 UL http://molpharm.aspetjournals.org/content/early/2010/06/17/mol.110.064394.abstract AB Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for Gαq, that is involved in regulating various vascular functions. To understand how RGS2 regulates foam cell formation, the present study identified signaling pathways controlled by 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 downregulation by LPS was partially recovered by TLR4 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 while RGS2 downregulation accelerated foam cell formation by LPS. Treatment of PKC-η pseudosubstrate weakened foam cell formation and recovered RGS2 downregulation by LPS. In addition, LPS or PMA stimulated PLD activity, and the pretreatment of PLD inhibitor weakened foam cell formation and recovered RGS2 downregulation. Inhibition of PLD2 expression by siRNA also weakened foam cell formation and partially recovered LPS-mediated RGS2 downregulation. On the other hand, PLD2 overexpression intensified RGS2 downregulation and foam cell formation by LPS. These results suggest that LPS causes foam cell formation by increasing PKC-η and PLD2 activity, by downregulating RGS2 expression via TLR4 dependently.The American Society for Pharmacology and Experimental Therapeutics