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THU0488 Microrna-34A and Microrna-155 Unbalance is Associated to IL-6/IL-6R and Vegf/Vegf-Rii Pathways in VEDOSS and Long Standing Systemic Sclerosis: Possible Epigenetic Regulators of Endothelial Dysfunction
  1. S. Alivernini1,
  2. S. Bosello2,
  3. S. Canestri1,
  4. C. Di Mario1,
  5. G. De Luca1,
  6. M.R. Gigante1,
  7. B. Tolusso1,
  8. G. Ferraccioli1
  1. 1Division of Rheumatology
  2. 2Catholic University of the Sacred Heart, Rome, Italy

Abstract

Background Endothelial dysfunction is a key feature of Systemic sclerosis (SSc). MicroRNAs (miRs) are novel post-transcriptional regulators implicated in SSc pathogenesis. MiR-34a and miR-155 are related to endothelial senescence and inflammation.

Objectives 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. Patients were divided into 3 different groups: SSc patients fulfilling the 1987 ACR criteria (n=10), SSc patients fulfilling the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) criteria (n=9) and patients with primary RP (n=8). Matched healthy controls (HC) (n=7) were enrolled.

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. Using HumanTargetScan cross-referenced methodology, IL-6 receptor (IL6-R) was selected as target of miR-34a and miR-155 while VEGF-RII as target of miR-155. Targets were experimentally confirmed by qPCR. VEGF, VEGF-RII, IL-6 and IL-6R plasma levels were determined by ELISA.

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

IL-6R and VEGF-RII expression is significantly lower in SSc and VEDOSS patients compared to primary RP (p=0.03 and p=0.03). Moreover, IL-6R/miR-155 and VEGF-RII/miR-155 ratios were significantly lower in SSc and VEDOSS compared to primary RP (p<0,0001 for all comparisons). IL-6r/miR-34a ratio was significantly lower only in SSc patients compared to primary RP as well as VEDOSS (p<0,0001 for both). VEGF plasma levels were significantly higher in SSc patients compared to HC (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. The expression of miR-34a directly correlated with the skin score value (R=0.52, p=0.03) in both SSc and VEDOSS patients and with IL-6 plasma levels (R=0.42, p=0.01).

Dividing SSc and VEDOSS patients according to the autoimmune profile, anti-Scl70+ patients have higher expression of miR-34a compared to anti-centromere+ patients (p=0.04). Furthermore, considering SSc related clinical vascular manifestations, patients with digital ulcers have significantly higher miR-34a expression compared to patients without ulcers (p=0,01). Moreover, SSc patients with skin ulcers have lower IL-6R/miR-34a ratio compared to patients without ulcers (p=0,02).

Conclusions MiR-34a and miR-155 expression is unbalanced in SSc and VEDOSS acting on IL-6/IL-6R and VEGF/VEGF-RII pathways. This contributes to a decreased expression of IL-6R and VEGF-RII associated to the increase of IL-6 and VEGF plasma levels characterizing different disease clinical features.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.4461

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