Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada; Departments of Medicine, London, Ontario N6A 4G5, Canada; Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei 230032, China.
Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada; Departments of Medicine, London, Ontario N6A 4G5, Canada.
J Biol Chem. 2010 Mar 26;285(13):9429-9436. doi: 10.1074/jbc.M109.071274. Epub 2010 Jan 22.
Lipopolysaccharides (LPS) induce tumor necrosis factor-alpha (TNF-alpha) production in cardiomyocytes, which contributes to myocardial depression during sepsis. However, the underlying mechanisms remain not fully understood. This study was undertaken to investigate the contribution of histone deacetylase (HDAC) to TNF-alpha expression in cardiomyocytes and the signaling mechanism of LPS-induced HDAC activation. Here, we show for the first time that LPS increases HDAC activity and that inhibition of HDAC decreases LPS-stimulated TNF-alpha expression via the accumulation of NF-kappaB/p65 at the TNF-alpha promoter in cardiomyocytes. Using a positive screen, we have further identified HDAC3 as a specific member of the HDAC family able to regulate TNF-alpha production. Furthermore, our data reveal that LPS-induced HDAC activity is mediated through reactive oxygen species from mitochondria and c-Src signaling. In summary, this study demonstrates a novel signaling mechanism by which LPS via mitochondrial reactive oxygen species/c-Src/HDAC3 pathways mediate TNF-alpha expression in cardiomyocytes.
脂多糖（LPS）诱导心肌细胞产生肿瘤坏死因子-α（TNF-α），这有助于脓毒症期间的心肌抑制。然而，其潜在机制仍不完全清楚。本研究旨在探讨组蛋白去乙酰化酶（HDAC）在心肌细胞中 TNF-α表达中的作用，以及 LPS 诱导的 HDAC 激活的信号机制。在这里，我们首次表明 LPS 增加了 HDAC 的活性，并且通过在心肌细胞中 TNF-α启动子处积累 NF-κB/p65，抑制 HDAC 可降低 LPS 刺激的 TNF-α表达。通过阳性筛选，我们进一步鉴定出 HDAC3 是能够调节 TNF-α产生的 HDAC 家族的特定成员。此外，我们的数据表明，LPS 诱导的 HDAC 活性是通过线粒体和 c-Src 信号转导中的活性氧来介导的。总之，本研究证明了一种新的信号机制，即 LPS 通过线粒体活性氧物质/c-Src/HDAC3 途径介导心肌细胞中 TNF-α的表达。
