Abstract：
Pulmonary arterial hypertension (PAH) mainly occurs as a result of abnormal proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Endothelial progenitor cell (EPC)-derived exosomes (Exos) (EPC-Exos) relieve PAH. However, there is still insufficient knowledge of whether EPC-Exos contribute to the pathological process of PAH, especially for PASMC repair. This study aimed to determine the effects of EPC-Exos on the proliferation, migration, and apoptosis of PASMCs and explore the possible underlying molecular mechanisms through bioinformatics analysis and in vitro testing. Bioinformatics analysis showed that the Ras signaling pathway and Exos were crucial in PAH. The PAH differential microRNAs (miRNAs) and miRNAs identified in EPC-Exos were intersected to obtain miR-21-5p. A target gene prediction program predicted mitofusin-2 (Mfn2) as a potential target of miR-21-5p. Cellular experiments demonstrated that EPC-Exos attenuated the viability, proliferation, migration, and apoptosis resistance of PASMCs under hypoxia. Mechanistically, EPC-Exos significantly upregulated Mfn2 expression and attenuated Ras-Raf-ERK1/2 signaling pathway activity. In conclusion, EPC-Exos suppress cell viability, proliferation, and migration and promote apoptosis in PASMCs under hypoxic conditions. It is possible to transport miR-21-5p to improve the expression of Mfn2 and inhibit the Ras-Raf-ERK1/2 signaling pathway directly or by targeting the expression of Mfn2. EPC-Exos are a potential therapeutic candidate for the treatment of PAH.
摘要：
肺动脉高压（PAH）主要是由于肺动脉平滑肌细胞（PASMCs）的异常增殖和凋亡抵抗所致。内皮祖细胞(EPC)衍生的外泌体(Exos)(EPC-Exos)缓解PAH。然而,关于EPC-Exos是否有助于PAH的病理过程的知识仍然不足，特别是PASMC的维修。本研究旨在确定EPC-Exos对增殖的影响，迁移,通过生物信息学分析和体外检测,探讨PASMCs细胞凋亡的可能分子机制。生物信息学分析表明，Ras信号通路和Exos在PAH中起着至关重要的作用。将PAH差异微小RNA(miRNA)和EPC-Exos中鉴定的miRNA相交以获得miR-21-5p。靶基因预测程序预测mitofusin-2（Mfn2）是miR-21-5p的潜在靶标。细胞实验表明，EPC-Exos减弱了生存力，扩散,迁移,缺氧条件下PASMCs的抗凋亡性。机械上,EPC-Exos显著上调Mfn2表达并减弱Ras-Raf-ERK1/2信号通路活性。总之,EPC-Exos抑制细胞活力，扩散,缺氧条件下PASMCs的迁移和促进细胞凋亡。有可能通过转运miR-21-5p来提高Mfn2的表达,直接或通过靶向Mfn2的表达来抑制Ras-Raf-ERK1/2信号通路。EPC-Exos是治疗PAH的潜在治疗候选物。
