PT  - JOURNAL ARTICLE
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
TI  - Protein kinase C-η and phospholipase D2 pathway regulates foam cell formation via regulator of G protein signaling 2
AID  - 10.1124/mol.110.064394
DP  - 2010 Jun 17
TA  - Molecular Pharmacology
PG  - mol.110.064394
4099  - http://molpharm.aspetjournals.org/content/early/2010/06/17/mol.110.064394.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/06/17/mol.110.064394.full
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