Exosomal 15-LO2 mediates hypoxia-induced pulmonary artery hypertension in vivo and in vitro

Min Zhang,Min Zhang,Huajian Li,Xiaodong Zheng,Xiufeng Yu,Min Mao,Min Mao,Wei Xin,Wei Xin,Daling Zhu,Daling Zhu,Lixin Zhang,Lixin Zhang,Cui Ma,Hongyue Zhang,Hongyue Zhang,Huajian Li,Ying Liu,Ying Liu

doi:10.1038/s41419-018-1073-0

Abstract

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.

Highlights

Pulmonary artery hypertension (PH) is a life-threatening disease characterized by the pathological manifestation of pulmonary vascular remodeling, which leads to enhanced right ventricular afterload, right heart failure, and eventually death[1]
It is unclear whether exosomes serve as extracellular vesicles in a paracrine or autocrine manner to participate in the dysfunction of pulmonary artery endothelial cells (PAECs) in pulmonary vascular homeostasis, as well as the cellular origin of exosomes and the role of PAEC-derived exosomes in the process of PH
The results indicated that GW4869 was prevented and reversed the vascular remodeling (Fig. 2a, b), reduced the density of pulmonary vasculature (Fig. 2c), elevated right ventricular hypertrophy, mean right ventricular systolic pressure (RVSP) (Fig. 2d), decreased the ratio of pulmonary artery acceleration time/ pulmonary artery ejection time (PAT/PET), and lowered pulmonary arterial velocity time integral (PAVTI), as compared with the vehicle group (Fig. 2e), while hypoxic PAECs-derived exosomes injection promoted the vascular remodeling, mean RVSP, and right ventricular hypertrophy which induced by hypoxia (Fig. S2)

Summary

Introduction

Pulmonary artery hypertension (PH) is a life-threatening disease characterized by the pathological manifestation of pulmonary vascular remodeling, which leads to enhanced right ventricular afterload, right heart failure, and eventually death[1]. The underlying mechanisms involved in the dysfunction of pulmonary artery endothelial cells (PAECs) in pulmonary vascular homeostasis and the progression of PH remain unclear. Evidence shows that exosomes from mesenchymal stromal cells in a paracrine manner inhibit inflammation in PH11. It is unclear whether exosomes serve as extracellular vesicles in a paracrine or autocrine manner to participate in the dysfunction of PAECs in pulmonary vascular homeostasis, as well as the cellular origin of exosomes and the role of PAEC-derived exosomes in the process of PH

Methods

Results

Conclusion