期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 28, 期 8, 页码 1519-1526出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.108.168682
关键词
sphingomyelin synthase 2; sphingomyelin; lipid rafts; NF kappa B; atherosclerosis
资金
- NHLBI NIH HHS [HL-69817, HL-64735] Funding Source: Medline
Background - NF kappa B has long been regarded as a proatherogenic factor, mainly because of its regulation of many of the proinflammatory genes linked to atherosclerosis. Metabolism of sphingomyelin (SM) has been suggested to affect NF kappa B activation, but the mechanism is largely unknown. SMS2 regulates SM levels in cell plasma membrane and lipid rafts and has a potential to regulate NF kappa B activation. Methods and Results - To investigate the role of SMS2 in NF kappa B activation we used macrophages from SMS2 knockout (KO) mice and SMS2 siRNA-treated HEK 293 cells. We found that NF kappa B activation and its target gene expression are attenuated in macrophages from SMS2 KO mice in response to lipopolysaccharide (LPS) stimulation and in SMS2 siRNA-treated HEK 293 cells after tumor necrosis factor (TNF)-alpha simulation. In line with attenuated NF kappa B activation, we found that SMS2 deficiency substantially diminished the abundance of toll like receptor 4 (TLR4)-MD2 complex levels on the surface of macrophages after LPS stimulation, and SMS2 siRNA treatment reduced TNF-alpha-stimulated lipid raft recruitment of TNF receptor-1 (TNFR1) in HEK293 cells. SMS2 deficiency decreased the relative amounts of SM and diacylglycerol (DAG) and increased ceramide, suggesting multiple mechanisms for the decrease in NF kappa B activation. Conclusions - SMS2 is a modulator of NF kappa B activation, and thus it could play an important role in NF kappa B-mediated proatherogenic process.
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