Background miRNAs are key players in a wide range of molecular and pathophysiological processes. Recently, several studies have examined their involvement in the pathogenesis of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). However, no study has evaluated the expression profile of miRNAs associated with the cardiovascular and the atherothrombotic risks observed in these autoimmune diseases.
Objectives To identify the miRNAs involved in the regulation of pro-inflammatory, prothrombotic and oxidative status in SLE and APS patients.
Methods In silico search was performed to find putative binding sites of miRNAs in various mRNA of proinflammatory factors (MCP-1, MIP-1a, IL-1b, -2, -6, -8, -17, -23, VEGF and tPA) prothrombotic proteins (TF and PAR2) and oxidative stress markers (peroxides production, antioxidant enzymes and mitochondrial activity) was performed. Neutrophils and monocytes were isolated from 11 APS patients, 17 SLE patients and 26 healthy donors. Selected miRNAs were quantified by RT-PCR. The expression of proinflammatory proteins was evaluated by flow cytometry and flow cytomix. Antioxidant enzymatic activity was also quantified. Carotid intima-media thickness (CIMT) was measured as a marker of early atherosclerosis.
Results In silico search reported miR-124a, -125a, -125b, -146a, -155, and -222 as candidates to regulate the expression of several proinflammatory proteins and oxidative status observed in SLE and APS patients. The expression levels of these miRNAs appeared significantly decreased in neutrophils from SLE and APS patients compared to healthy donors. However, only the miR-124a was found reduced in monocytes from SLE and APS patients, while miR-146a was increased. The expression levels of the miRNAs analyzed in SLE patients negatively correlated with the disease activity (SLEDAI) and the anti-dsDNA titers. In addition, an inverse correlation between anticardiolipin antibody titers and miRNAs expression was found in APS patients. Moreover, significant negative correlations between miRNAs expression and molecules related to mitochondrial dysfunction and oxidative stress were observed in APS monocytes and neutrophils. Inflammatory proteins showed specificity in their association with miRNAs depending on the disease analyzed, so that in APS inverse correlations were found with VEGF-R1, IL-8 and PAR2, while in LES significant correlations related to IL-2, IL-6, IL-10 and MCP.1 Low levels of miR-146a in APS and SLE neutrophils, and miR-155 in APS neutrophils, were associated with pathological CIMT. The presence of thrombotic events in APS and SLE was associated with low levels of miR-146a and miR-155 in neutrophils and monocytes.
Conclusions miRNAs differentially expressed in monocytes and neutrophils from APS and SLE patients correlate with markers of autoimmunity, inflammation, thrombosis and oxidative stress, and are associated with atherothrombotic processes. Therefore, these miRNAs might be considered potential biomarkers of pro-inflammatory pathology in both atherosclerosis and autoimmune diseases.
Acknowledgements Supported by P08-CVI-04234, PI12/01511 and PI11/00566
Disclosure of Interest None Declared
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