MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors

Abstract

Background: Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes. Methods: 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. Results: Our study found: 1) miR-26 and miR-let-7d levels were significantly lower in SSc-PAH (n = 12) versus SSc without PAH (SSc-noPAH) patients (n = 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. Conclusions: 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.

MicroRNAs in idiopathic inflammatory myopathies: state-of-the-art and future perspectives

“…In systemic sclerosis (SSc), miR-21, miR-145, miR-92a, miR4458, miR-155, and miR-202-3p upregulation is involved in pro-fibrotic pathways affecting the expression of TGFβ, metalloproteases, collagen production, and fibroblast survival. Interestingly, the circulating miRNA profile proved to be different between patients with a diffuse cutaneous form and those with a limited cutaneous one [24], and a differential miRNA expression was also found in SSc patients with pulmonary arterial hypertension (PAH) compared with those without as demonstrated in a recent study by Zaaroor Levy et al [25 ▪ ] who found lower miR-26 and miR-let-7d circulating levels in patients with PAH compared with SSc-noPAH patients. Moreover, Wuttge et al [26] showed a negative correlation between NT-pro-BNP values and miR-20a-5p or mir-203a-3p expression making them possible disease biomarkers.…”

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again

“…Moreover, levels of TGF-β1 are decreased in SSc-PAH as compared to SSc. Increased levels of TGF-β2 and TGF-β 3 were observed in both SSc and SSc-PAH patients, but SSc-PAH had a higher level of TGF-β2 and TGF-β3 compared to SSc [119] Levy et al found that miR-26 and miR-let-7d levels were significantly decreased in SSc-PAH versus SSc without PAH and bioinformatic analysis showed that both miRNAs-regulated genes belong to TGF-β signaling pathway or Smad binding gene sets [120]. Although mutations of TGF-β receptor genes contribute to idiopathic and familial PAH, there is lack of association between TGF-β receptor gene polymorphisms and SSc-PAH.…”

Frontiers of Targeted Therapy and Predictors of Treatment Response in Systemic Sclerosis

“…Zaaroor Levy et al studied the circulating miRNAs that may differentiate between SSc patients with and without pulmonary arterial hypertension (PAH) and assessed their expression in plasma, white blood cells, and dermal myofibroblasts [ 5 ]. They demonstrate that plasma levels of miR-26 and miR-let-7d are decreased in SSc-PAH patients compared to SSc patients without PAH.…”