Oncotarget

Research Papers: Pathology:

The activation of EGFR promotes myocardial tumor necrosis factor-α production and cardiac failure in endotoxemia

Xuegang Sun, Jiani Liang, Xueqing Yao, Chunhua Lu, Tianyu Zhong, Xiaoyang Hong, Xiaofei Wang, Wenjuan Xu, Miaoning Gu and Jing Tang _

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Oncotarget. 2015; 6:35478-35495. https://doi.org/10.18632/oncotarget.6071

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Abstract

Xuegang Sun1,2,*, Jiani Liang1,*, Xueqing Yao3,*, Chunhua Lu1, Tianyu Zhong4, Xiaoyang Hong5, Xiaofei Wang1, Wenjuan Xu2, Miaoning Gu1 and Jing Tang1

1 The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

2 The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China

3 The Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, Guangdong, China

4 The Department of Laboratory Medicine, First Affiliated Hospital of Ganna Medical University, Ganzhou, Jiangxi, China

5 The Department of Intensive Care Unit, BaYi Children’s Hospital, Beijing Military General Hospital, Beijing, China

* These authors have contributed equally to this work

Correspondence to:

Jing Tang, email:

Keywords: sepsis, EGFR, tumor necrosis factor-alpha, cardiac failure, Pathology Section

Received: June 30, 2015 Accepted: September 28, 2015 Published: October 10, 2015

Abstract

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.


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