The activation of EGFR promotes myocardial tumor necrosis factor-α production and cardiac failure in endotoxemia.
The activation of EGFR promotes myocardial tumor necrosis factor-α production and cardiac failure in endotoxemia.
复制标题
DOI：
10.18632/oncotarget.6071
复制
发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Sun X;Liang J;Yao X;Lu C;Zhong T;Hong X;Wang X;Xu W;Gu M;Tang J
为了研究脓毒症期间 EGFR 激活对 TNF-α 产生和心脏功能障碍发生的影响，应用 PD168393 和厄洛替尼（均为 EGFR 抑制剂）来减少心肌细胞中 TNF-α 的产生以及 LPS 诱导的 ERK1/2 和 p38 磷酸化。通过体外特异性敲低EGFR的表达进一步证明了这些结果。 TAPI-1（一种 TNF-α 转换酶（TACE）抑制剂）和 TGF-α 中和抗体均可抑制 LPS 处理后 EGFR 的激活和 TNF-α mRNA 的生成。 TAPI-1 也可以抑制 LPS 引起的 TGF-α 增加。另一方面，外源性TGF-α响应LPS增加了TNF-α mRNA的表达，并部分逆转了TAPI-1对TNF-α mRNA表达的抑制作用，表明心肌细胞中LPS对EGFR的反式激活需要TACE和TGF-α的帮助。在内毒素血症小鼠中，抑制 EGFR 的激活不仅可以减少心肌中 TNF-α 的产生，还可以改善左心室泵功能，改善心功能不全，最终提高生存率。所有这些结果为EGFR如何调节心肌细胞中TNF-α的产生提供了新的见解，并为脓毒症心功能障碍的治疗提供了潜在的新靶点。
To study the effect of EGFR activation on the generation of TNF-α and the occurrence of cardiac dysfuncetion during sepsis, PD168393 and erlotinib (both are EGFR inhibitors) were applied to decreased the production of TNF-α and phosphrylation of ERK1/2 and p38 induced by LPS in cardiomyocytes. These results were further proved by specifically knocked down the expression of EGFR in vitro. Both TAPI-1, a TNF-α converting enzyme (TACE) inhibitor, and TGF-α neutralizing antibody could inhibit the activation of EGFR and the generation of TNF-α mRNA after LPS treatment. The increase of TGF-α in response to LPS could also be suppressed by TAPI-1. On the other hand, exogenous TGF-α increased the expression of TNF-α mRNA and partially reversed the inhibitory effect of TAPI-1 on expression of TNF-α mRNA in response to LPS indicating that the transactivation of EGFR by LPS in cardiomyocytes needs the help of TACE and TGF-α. In endotoxemic mice, inhibition the activation of EGFR not only decreased TNF-α production in the myocardium but also improved left ventricular pump function and ameliorated cardiac dysfunction and ultimately improved survival rate. All these results provided a new insight of how EGFR regulation the production of TNF-α in cardiomyocytes and a potential new target for the treatment of cardiac dysfunction in sepsis.