Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter
Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter
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DOI：
10.1086/688761
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发表时间：
2016-12-01
影响因子：
2.6
通讯作者：
Garcia, Joe G. N.
中科院分区：
文献类型：
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作者：
Elangovan, Venkateswaran Ramamoorthi;Camp, Sara M.;Garcia, Joe G. N.
机械通气是急性呼吸窘迫综合征（ARDS）患者的救生干预措施，但不幸的是，它也会导致过度的机械应力和肺生理和结构完整性受损。我们已经在其他地方建立了烟酰胺磷酸核糖基转移酶（NAMPT）的转录和分泌增加，以及其直接结合的toll样受体4（TLR 4）在这种破坏性综合征的进展中的关键作用;然而，调节呼吸机诱导的肺损伤（VILI）中的这一关键基因没有得到很好的表征。基于表观遗传学在NAMPT启动子和5 'UTR内VILI和CpG位点富集中的新兴作用，我们假设NAMPT表达和下游转录事件受到表观遗传机制的影响。与此同时，人肺动脉内皮细胞的过度机械应力或脂多糖（LPS）处理导致NAMPT启动子中DNA甲基化水平降低和基因转录增加。组蛋白去乙酰化酶抑制剂A或Sirt-1沉默RNA减弱LPS诱导的NAMPT表达。此外，重组NAMPT给药诱导TLR 4依赖性的整体H3 K9低乙酰化。这些研究表明，NAMPT在VILI和ARDS中存在复杂的表观遗传调控网络，并提出了对抗VILI和ARDS的新策略。
Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator-induced lung injury (VILI) is not well characterized. On the basis of an emerging role for epigenetics in enrichment of VILI and CpG sites within the NAMPT promoter and 5'UTR, we hypothesized that NAMPT expression and downstream transcriptional events are influenced by epigenetic mechanisms. Concomitantly, excessive mechanical stress of human pulmonary artery endothelial cells or lipopolysaccharide (LPS) treatment led to both reduced DNA methylation levels in the NAMPT promoter and increased gene transcription. Histone deacetylase inhibition by trichostatin A or Sirt-1-silencing RNA attenuates LPS-induced NAMPT expression. Furthermore, recombinant NAMPT administration induced TLR4-dependent global H3K9 hypoacetylation. These studies suggest a complex epigenetic regulatory network of NAMPT in VILI and ARDS and open novel strategies for combating VILI and ARDS.