The activation of EGFR promotes myocardial tumor necrosis factor-α production and cardiac failure in endotoxemia.
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.
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.|The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Xuegang
X
Sun
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Jiani
J
Liang
The Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, Guangdong, China.
Xueqing
X
Yao
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Chunhua
C
Lu
The Department of Laboratory Medicine, First Affiliated Hospital of Ganna Medical University, Ganzhou, Jiangxi, China.
Tianyu
T
Zhong
The Department of Intensive Care Unit, BaYi Children's Hospital, Beijing Military General Hospital, Beijing, China.
Xiaoyang
X
Hong
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Xiaofei
X
Wang
The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Wenjuan
W
Xu
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Miaoning
M
Gu
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Jing
J
Tang
D000818:Animals; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; C509204:PD168393; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors
EGFR; Pathology Section; cardiac failure; sepsis; tumor necrosis factor-alpha