School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease National Sun Yat-sen University Kaohsiung Taiwan.
Division of Cardiology, Department of Internal Medicine Chi Mei Medical Center Tainan Taiwan.
J Am Heart Assoc. 2023 Dec 5;12(23):e031435. doi: 10.1161/JAHA.123.031435. Epub 2023 Nov 28.
Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)-related PAH.
During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD-related PAH. Next-generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR-21, miR-139-5p, miR-155-5p, let-7f-5p, miR-328-3p, miR-330-3p, and miR-103a-3p in patients with CHD-related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR-21 exhibited the highest expression in patients with CHD-related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD-related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR-21. Suppressing miR-21 rescued the shear stress-induced downregulation of the RAS/phosphatidylinositol 3-kinase/protein kinase B pathway, leading to a mitigation of apoptosis.
Our study identified a pronounced expression of transpulmonary exosomal miR-21, particularly in patients with CHD-related PAH, through next-generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR-21 in the pathophysiology of PAH.
肺动脉高压（PAH）是一种以复杂发病机制为特征的致命疾病。含有 microRNAs（miRs）的外泌体已成为一种新的生物标志物。肺循环中外泌体 miR 提供了有价值的见解，可以深入了解肺循环的微环境。因此，我们旨在探索肺循环中外泌体 miR 作为特发性 PAH 和先天性心脏病（CHD）相关 PAH 之间鉴别因素的潜力。
在右心导管检查过程中，我们在 25 名特发性 PAH 患者和 20 名 CHD 相关 PAH 患者的肺动脉中收集外泌体。下一代测序确定了几个候选外泌体 miR。通过定量聚合酶链反应，我们验证了这些 miR 的表达，并揭示了 CHD 相关 PAH 患者 miR-21、miR-139-5p、miR-155-5p、let-7f-5p、miR-328-3p、miR-330-3p 和 miR-103a-3p 的表达显著升高，与特发性 PAH 患者相比。在这些 miR 中，miR-21 在 CHD 相关 PAH 患者中的表达最高。在包括 10 名特发性 PAH 患者和 8 名 CHD 相关 PAH 患者的外部队列中进一步证实了这些发现。使用模拟肺内皮细胞经历的切应力的体外流模型，我们观察到 miR-21 的显著上调。抑制 miR-21 挽救了切应力诱导的 RAS/磷酸肌醇 3-激酶/蛋白激酶 B 通路的下调，从而减轻了细胞凋亡。
通过下一代测序分析，我们发现了明显表达的肺循环外泌体 miR-21，特别是在 CHD 相关 PAH 患者中。需要进一步研究来阐明 miR-21 参与 PAH 病理生理学的调节机制。
