Lipopolysaccharide Induces Human Pulmonary Micro-Vascular Endothelial Apoptosis via the YAP Signaling Pathway.
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.
Department of Orthopedics, Shanghai Fengxian Central Hospital, Branch of The Sixth People's Hospital Affiliated to Shanghai Jiao Tong University Shanghai, China.
Lei
L
Yi
Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Xiaoqin
X
Huang
Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Feng
F
Guo
Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Zengding
Z
Zhou
Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Mengling
M
Chang
Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Jiajun
J
Tang
Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Jingning
J
Huan
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis; D002467:Cell Nucleus / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D014157:Transcription Factors; D000072160:Tumor Protein p73; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D008070:Lipopolysaccharides; D010750:Phosphoproteins; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
P73; Yes-associated protein; apoptosis; endothelial cells; lipopolysaccharide