Lipopolysaccharide Induces Human Pulmonary Micro-Vascular Endothelial Apoptosis via the YAP Signaling Pathway.

Lei Yi,Feng Guo,Mengling Chang,Jiajun Tang,Xiaoqin Huang,Zengding Zhou,Jingning Huan

doi:10.3389/fcimb.2016.00133

Abstract

Gram-negative bacterial lipopolysaccharide (LPS) induces a pathologic increase in lung vascular leakage under septic conditions. LPS-induced human pulmonary micro-vascular endothelial cell (HPMEC) apoptosis launches and aggravates micro-vascular hyper-permeability and acute lung injury (ALI). Previous studies show that the activation of intrinsic apoptotic pathway is vital for LPS-induced EC apoptosis. Yes-associated protein (YAP) has been reported to positively regulate intrinsic apoptotic pathway in tumor cells apoptosis. However, the potential role of YAP protein in LPS-induced HPMEC apoptosis has not been determined. In this study, we found that LPS-induced activation and nuclear accumulation of YAP accelerated HPMECs apoptosis. LPS-induced YAP translocation from cytoplasm to nucleus by the increased phosphorylation on Y357 resulted in the interaction between YAP and transcription factor P73. Furthermore, inhibition of YAP by small interfering RNA (siRNA) not only suppressed the LPS-induced HPMEC apoptosis but also regulated P73-mediated up-regulation of BAX and down-regulation of BCL-2. Taken together, our results demonstrated that activation of the YAP/P73/(BAX and BCL-2)/caspase-3 signaling pathway played a critical role in LPS-induced HPMEC apoptosis. Inhibition of the YAP might be a potential therapeutic strategy for lung injury under sepsis.

Highlights

Sepsis is a serious consequence of Gram-negative bacterial infection in critically ill patients (Wendel et al, 2007)
We found that Yes-associated protein (YAP) was activated during LPS-induced human pulmonary micro-vascular endothelial cell (HPMEC) apoptosis via the phosphorylation on Y357, which accumulated in the nucleus and bound transcription factor P73
We showed that YAP accelerated LPS-induced HPMEC apoptosis through its phosphorylation activation and accumulation in endothelial cells (ECs) nucleus

Summary

Introduction

Sepsis is a serious consequence of Gram-negative bacterial infection in critically ill patients (Wendel et al, 2007). Lipopolysaccharide (LPS), as a major component of the outer membrane of Gram-negative bacteria, induces a multitude of endothelial dysfunctions, such as the coagulation activation and vascular barrier disruption (Zhou et al, 2013; Yi et al, 2016). LPS-induced endothelial cells (ECs) apoptosis and detachment from the vessel basement membrane deteriorates LPS-induced micro-vascular injury and further induces dysfunction in multiple organs (Hotchkiss et al, 2002). Recent studies have showed that the sepsis-induced acute lung injury (ALI) is characterized by apoptosis of the LPS Induces EC Apoptosis via YAP lung micro-vascular endothelial cells (Gill et al, 2014, 2015). The signaling transduction pathways implicated in LPS-induced human pulmonary micro-vascular endothelial cell (HPMEC) apoptosis remains unclear. We aim to define the molecular mechanism by which LPS induces apoptosis of HPMECs in vitro

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