Estephan Leonard E, Genuardi Michael V, Kosanovich Chad M, Risbano Michael G, Zhang Yingze, Petro Nancy, Watson Annie, Al Aaraj Yassmin, Sembrat John C, Rojas Mauricio, Goncharov Dmitry A, Simon Marc A, Goncharova Elena A, Vaidya Anjali, Smith Akaya, Mazurek Jeremy, Han Yuchi, Chan Stephen Y
1 Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
2 Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Pulm Circ. 2019 Apr-Jun;9(2):2045894019840646. doi: 10.1177/2045894019840646.
Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06-0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.
肺动脉高压（PH）是一种异质性血管疾病，由具有重叠临床表型的亚型组成。微小RNA是一类负向调节基因表达的小非编码RNA，已成为PH发病机制的调节因子。已知肌肉特异性微小RNA（miR）-204在患病的肺动脉平滑肌细胞（PASMC）中减少，从而促进增殖并导致PH。跨肺血管床循环血浆miR-204的变化可能为观察到的细胞内miR-204减少提供机制上的见解，并有助于区分PH亚型。对91例世界卫生组织（WHO）I组肺动脉高压（PAH）（n = 47）、II组PH（n = 22）或无PH（n = 22）患者的连续肺血管部位的miR-204水平进行了定量分析。采集右心房/上腔静脉、肺动脉和肺毛细血管楔压处的血液。分离外周血单核细胞（PBMC）（每组n = 5）。还在体外对PAH-PASMC分泌的miR-204进行了定量分析。仅在I组患者中，miR-204浓度沿肺血管依次升高（对数倍变化斜率 = 0.22 [95% CI = 0.06 - 0.37]，P = 0.008）。PBMC显示PH组间miR-204变化不显著（P = 0.12）。与对照组相比，培养的PAH-PAMSC细胞内miR-204减少（P = 0.0004），而细胞外miR-204则相反增加（P = 0.0018）。I组而非II组PH患者中循环miR-204在肺血管中的逐步升高表明各亚型之间肌肉特异性病理生物学存在差异。考虑到miR-204在PH中的已知重要性，这些发现可能提示I组PAH中PASMC对miR-204的病理性分泌，从而解释了细胞内miR-204浓度降低的原因。
