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A3.21 MicroRNA-34a and microRNA-155 in Systemic Sclerosis: possible epigenetic biomarkers of endothelial dysfunction in VEDOSS and long-standing disease
  1. Stefano Alivernini,
  2. Silvia Laura Bosello,
  3. Giacomo De Luca,
  4. Silvia Canestri,
  5. Clara Di Mario,
  6. Maria Rita Gigante,
  7. Barbara Tolusso,
  8. Gianfranco Ferraccioli
  1. Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy

Abstract

Background and Objectives MicroRNAs (miRs) are a novel class of post-transcriptional regulators that have been implicated in the pathogenesis of Systemic sclerosis (SSc). MiR-34a and miR-155 were found to be related to endothelial senescence and inflammation. The aim of this study was to investigate the expression of miR-34a and miR-155 in peripheral blood mononuclear cells (PBMCs) in SSc.

Methods Twenty-seven consecutive patients with Raynaud phenomenon (RP) were enrolled in this exploratory study. Particularly, patients were divided into 3 different study cohorts: patients with primary RP with normal capillaroscopic findings and without any autoantibodies (n = 8), SSc patients fulfilling the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) criteria (n = 9) and SSc patients fulfilling the 1987 ACR criteria (n = 10) respectively. Gender and age matched healthy individuals (n = 7) were enrolled as controls.

Expression of miR-34a and miR-155 was evaluated by qPCR on PBMCs isolated by gradient hystopaque technique from peripheral blood (PB) of all patients. To identify miR-34a HumanTargetScan cross-referenced was employed. Identified targets were experimentally verified by qPCR. VEGF, VEGF-RII, IL-6 and IL-6R plasma levels were determined through ELISA.

Results MiR-155 is overexpressed either in VEDOSS (p = 0.0002) and SSc (p = 0.04) patients compared to healthy controls. MiR-34a expression is increased only in SSc compared to healthy controls (p = 0.01). Patients with primary RP did not differ according to miR-155 and miR-34a expression from healthy controls (p>0.05)

Dividing SSc and VEDOSS patients according to the autoimmune profile, anti-Scl70 + have higher expression of miR-34a compared to anti-centromere + patients (p = 0.04). Furthermore, stratifying SSc patients according to the clinical vascular manifestations, SSc patients with active and/or previous digital ulcers have significantly higher miR-34a expression compared to patients without ulcers history (p = 0.01). Finally the expression of miR-34a directly correlated with the skin score value (R = 0.52, p = 0.032) in both SSc and VEDOSS patients and with IL-6 plasma levels (R = 0.42, p = 0.01).

Using HumanTargetScan cross-referenced methodology, IL-6 receptor (IL6-R) was selected as target of miR-34a. IL6-R gene expression was found to be significantly higher in VEDOSS compared to SSc patients (p = 0.02). VEGF plasma levels were significantly higher in SSc patients compared to healthy controls (p = 0.01) as well as IL-6 plasma levels (p = 0.02), whereas no significant differences were found in VEGF-RII and IL-6R plasma levels comparing the different patients’ cohorts.

Conclusions Epigenetic factors, as miR-34a and miR-155 are deregulated in SSc and VEDOSS. Their expression analysis could help to differentiate different disease phases and between primary and SSc associated RP.

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