gw-4869 and Hypertension--Pulmonary

Our previous studies have shown that 15-LO2/15-HETE induced by hypoxia played an important role in pulmonary arterial hypertension (PH). However, the transportations of 15-LO2/15-HETE among the cells remain elusive. In this study, we investigated the specific involvement of 15-LO2-containing exosomes in the overproliferation of pulmonary artery endothelial cells (PAECs) induced by hypoxia and the underlying mechanism. In vitro, 15-LO2 was abundantly expressed and enriched in exosomes secreted from hypoxic PAECs, which subsequently activated the STAT3 signaling pathway, resulting in a robust increase in PAECs proliferation. In vivo treatment with the exosomes inhibitor GW4869 protected the pulmonary vascular homeostasis from dysfunctional and abnormal remodeling. Moreover, 15-LO2 was ubiquitinated under hypoxia, and further inhibition of the ubiquitin-proteasome system significantly suppressed PAECs proliferation, suggesting that ubiquitination of 15-LO2 may contribute to its sorting into exosomes. Overall, these findings indicate a previously unrecognized effect of exosomes and the cargo 15-LO2 in pulmonary vascular homeostasis on the pathogenesis of PH.

Topics: Aniline Compounds; Animals; Arachidonate 15-Lipoxygenase; Benzylidene Compounds; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelial Cells; Exosomes; Hydroxyeicosatetraenoic Acids; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Inbred C57BL; Proteasome Endopeptidase Complex; Pulmonary Artery; Signal Transduction; Ubiquitin; Ubiquitination