Yes-associated protein (YAP) signaling regulates lipopolysaccharide-induced tissue factor expression in human endothelial cells.
Abstract
Sepsis-induced acute lung injury (ALI) is characterized by fibrin deposition, which indicates the local activation of coagulation. Tissue factor (TF), expressed in the pulmonary microvasculature, acts as a critical initiator of blood coagulation and ALI in sepsis. The molecular mechanism of lipopolysaccharide (LPS)-induced TF expression in endothelial cells (ECs), however, has not been determined. In this study, we implicate the Rho-associated protein kinase (ROCK)/Yes associated protein (YAP)/early growth response (Egr-1) signaling pathway in LPS-induced TF expression in vitro and in sepsis-induced ALI in vivo. Human umbilical vein ECs incubated with LPS were pretreated with or without the ROCK inhibitor Y-27632, a YAP small, interfering RNA (siRNA) and an Egr-1 siRNA. ROCK, YAP and Egr-1 signaling-induced protein expression was investigated by Western blot. The LPS-induced activation of YAP was analyzed by an immunofluorescent assay. Furthermore, we intratracheally injected YAP siRNA to assess septic ALI in mice by hematoxylin and eosin staining. LPS rapidly induced ROCK activation and increased TF expression in ECs. LPS caused YAP shuttling into the nuclei of ECs and combined with Egr-1 via the activation of ROCK. Furthermor...Continue Reading
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