Calcium-independent phospholipase A2beta-Akt signaling is involved in lipopolysaccharide-induced NADPH oxidase 1 expression and foam cell formation.
Foam cell formation is the most important process in atherosclerosis, and low density lipoprotein oxidation by reactive oxygen species (ROS) is the key step in the conversion of macrophages to foam cells. This study reveals the control mechanism of the gene for NADPH oxidase 1 (Nox1), which produces ROS in the formation of foam cells by stimulating TLR4. Treatment of macrophages by the TLR4 agonist LPS stimulated ROS production and ROS-mediated macrophage to foam cell conversion. This LPS-induced ROS production and foam cell formation could be abrogated by pretreatment of macrophages with N-acetyl cysteine or apocynin. LPS increased Nox1 promoter activity, and resultant expression of mRNA and protein. Small interfering RNA mediated inhibition of Nox1 expression decreased LPS-induced ROS production and foam cell formation. LPS-mediated Nox1 expression and the responses occurred in a calcium-independent phospholipase A(2) (iPLA(2))-dependent manner. The iPLA(2)beta-specific inhibitor S-BEL or iPLA(2)beta small interfering RNA attenuated LPS-induced Nox1 expression, ROS production, and foam cell formation. In addition, activation of iPLA(2)beta by LPS caused Akt phosphorylation and was followed by increased Nox1 expression. These results suggest that the binding of LPS and TLR4 increases Nox1 expression through the iPLA(2)beta-Akt signaling pathway, and control ROS production and foam cell formation.
Lee
Sun-Hye
SH
Aging-associated Vascular Disease Research Center, Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, South Korea.
Park
Dae-Weon
DW
Park
Sung Chul
SC
Park
Yun-Ki
YK
Hong
Seong Yeon
SY
Kim
Jae-Ryong
JR
Lee
Chu-Hee
CH
Baek
Suk-Hwan
SH
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D020013:Calcium Signaling / Q000276:immunology; D002460:Cell Line; D005434:Flow Cytometry; D005487:Foam Cells / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D054513:Group IV Phospholipases A2 / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018613:Microscopy, Confocal; D009247:NADH, NADPH Oxidoreductases / Q000276:immunology* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D054513:Group IV Phospholipases A2