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

Abstract

To study the effect of EGFR activation on the generation of TNF-a and the occurrence of cardiac dysfuncetion during sepsis, PD168393 and erlotinib (both are EGFR inhibitors) were applied to decreased the production of TNF-a 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-a converting enzyme (TACE) inhibitor, and TGF-a neutralizing antibody could inhibit the activation of EGFR and the generation of TNF-a mRNA after LPS treatment. The increase of TGF-a in response to LPS could also be suppressed by TAPI-1. On the other hand, exogenous TGF-a increased the expression of TNF-a mRNA and partially reversed the inhibitory effect of TAPI-1 on expression of TNF-a mRNA in response to LPS indicating that the transactivation of EGFR by LPS in cardiomyocytes needs the help of TACE and TGF-a. In endotoxemic mice, inhibition the activation of EGFR not only decreased TNF-a 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-a in cardiomyocytes and a potential new target for the treatment of cardiac dysfunction in sepsis.