Zaaroor Levy Mor, Rabinowicz Noa, Yamila Kohon Maia, Shalom Avshalom, Berl Ariel, Hornik-Lurie Tzipi, Drucker Liat, Tartakover Matalon Shelly, Levy Yair
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Autoimmune Research Laboratory, Meir Medical Center, Kfar Saba 4428164, Israel.
Biomedicines. 2022 Mar 8;10(3):629. doi: 10.3390/biomedicines10030629.
Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes.
We searched for circulating miRNAs that would constitute biomarkers in SSc patients with PAH (SSc-PAH). We compared miRNA levels and laboratory parameters while evaluating miRNA levels in white blood cells (WBCs) and myofibroblasts.
Our study found: 1) miR-26 and miR-let-7d levels were significantly lower in SSc-PAH ( = 12) versus SSc without PAH (SSc-noPAH) patients ( = 25); 2) a positive correlation between miR-26 and miR-let-7d and complement-C3; 3) GO-annotations of genes that are miR-26/miR-let-7d targets and that are expressed in myofibroblast cells, suggesting that these miRNAs regulate the TGF-β-pathway; 4) reduced levels of both miRNAs accompanied fibroblast differentiation to myofibroblasts, while macitentan (endothelin receptor-antagonist) increased the levels. WBCs of SSc-noPAH and SSc-PAH patients contained equal amounts of miR-26/miR-let-7d. During the study, an echocardiograph that predicted PAH development, showed increased pulmonary artery pressure in three SSc-noPAH patients. At study initiation, those patients and an additional SSc-noPAH patient, who eventually developed PAH, had miR-let-7d/miR-26 levels similar to those of SSc-PAH patients. This implies that reduced miR-let-7d/miR-26 levels might be an early indication of PAH.
miR-26 and miR-let-7d may be serological markers for SSc-PAH. The results of our study suggest their involvement in myofibroblast differentiation and complement pathway activation, both of which are active in PAH development.
肺动脉高压（PAH）是系统性硬化症（SSc）患者死亡的主要原因。早期检测可能改善患者预后。
我们寻找可作为PAH合并SSc（SSc-PAH）患者生物标志物的循环miRNA。我们比较了miRNA水平和实验室参数，同时评估了白细胞（WBC）和成肌纤维细胞中的miRNA水平。
我们的研究发现：1）与无PAH的SSc（SSc-noPAH）患者（n = 25）相比，SSc-PAH患者（n = 12）的miR-26和miR-let-7d水平显著降低；2）miR-26和miR-let-7d与补体C3呈正相关；3）miR-26/miR-let-7d靶基因以及在成肌纤维细胞中表达的基因的GO注释，表明这些miRNA调节TGF-β信号通路；4）两种miRNA水平降低伴随着成纤维细胞向肌成纤维细胞的分化，而马昔腾坦（内皮素受体拮抗剂）可提高其水平。SSc-noPAH和SSc-PAH患者的白细胞中miR-26/miR-let-7d含量相等。在研究期间，一台预测PAH发展的超声心动图显示，3例SSc-noPAH患者的肺动脉压力升高。在研究开始时，这些患者以及另外1例最终发展为PAH的SSc-noPAH患者的miR-let-7d/miR-26水平与SSc-PAH患者相似。这意味着miR-let-7d/miR-26水平降低可能是PAH的早期迹象。
miR-26和miR-let-7d可能是SSc-PAH的血清学标志物。我们的研究结果表明它们参与了肌成纤维细胞分化和补体途径激活，这两者在PAH发展过程中均起作用。
