Plasma exosomes confer hypoxic pulmonary hypertension by transferring LOX-1 cargo to trigger phenotypic switching of pulmonary artery smooth muscle cells
Plasma exosomes confer hypoxic pulmonary hypertension by transferring LOX-1 cargo to trigger phenotypic switching of pulmonary artery smooth muscle cells
复制标题
血浆外泌体通过转移 LOX-1 货物来触发肺动脉平滑肌细胞的表型转换，从而导致缺氧性肺动脉高压
DOI：
10.1016/j.bcp.2022.115350
复制
发表时间：
2022
影响因子：
5.8
通讯作者：
Chang-Ping Hu
中科院分区：
文献类型：
--
作者：
Ning Huang;Di Wang;Tian-Tian Zhu;Xiao-Yue Ge;Hong Liu;Mao-Zhong Yao;Yan-Zi Guo;Jun Peng;Qing Wang;Zheng Zhang;Chang-Ping Hu
肺血管重构（PVR）是肺动脉高压（PH）的病理基础，是肺动脉平滑肌细胞（PASMCs）表型转换的结果，但其机制尚不完全清楚。外泌体是一种新型转移机制，能够将其货物输送到受体细胞，最近被发现与包括PH在内的心血管疾病有关。血浆来源的外泌体是否驱动PASMC表型转换以及外泌体输送什么货物这两个关键问题，然而，仍然不清楚。在此，通过透射电子显微镜和蛋白质检测，我们第一次，其特征在于凝集素样氧化低密度脂蛋白受体-1（LOX-1）作为一种新的货物血浆来源的外泌体在PH.与LOX-1敲除（Olr 1-/-）大鼠来源的外泌体，我们证明，外泌体LOX-1可以转移到PASMCs，从而引起细胞表型转换。重要的是，Olr 1-/-大鼠没有表现出细胞表型转换，并且发生了不太严重的PH，但是向Olr 1-/-大鼠施用野生型而不是Olr 1-/-外泌体再现了PH的表型，具有稳健的PASMC表型转换。我们还发现，外泌体LOX-1通过ERK 1/2-KLF 4信号轴触发PASMCs表型转换、PVR和最终PH。这项研究已经证明血浆来源的外泌体通过将LOX-1递送到PASMC中来赋予PH。因此，外泌体LOX-1代表了PH预防和治疗的新的可利用靶标。
The pulmonary vascular remodeling (PVR), the pathological basis of pulmonary hypertension (PH), entails pulmonary artery smooth muscle cells (PASMCs) phenotypic switching, but appreciation of the underlying mechanisms is incomplete. Exosomes, a novel transfer machinery enabling delivery of its cargos to recipient cells, have been recently implicated in cardiovascular diseases including PH. The two critical questions of whether plasma-derived exosomes drive PASMCs phenotypic switching and what cargo the exosomes transport, however, remain unclear. Herein, by means of transmission electron microscopy and protein detection, we for the first time, characterized lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) as a novel cargo of plasma-derived exosomes in PH. With LOX-1 knockout (Olr1-/-) rats-derived exosomes, we demonstrated that exosomal LOX-1 could be transferred into PASMCs and thus elicited cell phenotypic switching. Of importance,Olr1-/-rats exhibited no cell phenotypic switching and developed less severe PH, but administration of wild type rather thanOlr1-/-exosomes toOlr1-/-rats recapitulated the phenotype of PH with robust PASMCs phenotypic switching. We also revealed that exosomal LOX-1 triggered PASMCs phenotypic switching, PVR and ultimately PH via ERK1/2-KLF4 signaling axis. This study has generated proof that plasma-derived exosomes confer PH by delivering LOX-1 into PASMCs. Hence, exosomal LOX-1 represents a novel exploitable target for PH prevention and treatment.