Background miRNAs are key players in pathophysiological processes, but no previous studies have investigated their asscociation with the cardiovascular and atherothrombotic risks observed in primary antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE).
Objectives To characterize the miRNAs involved in pro-inflammatory, prothrombotic and pro-oxidative status in SLE and APS patients.
Methods In silico search was performed and six putative miRNAs regulating factors involved in the proinflammatory and pro-oxidative status of APS and SLE patients (miR-124a, -125a, -125b, -146a, -155, and -222) were selected and quantified by RT-PCR in neutrophils, lymphocytes and monocytes from 15 APS and 22 SLE patients, and 26 healthy donors. Pro-inflammatory and prothrombotic proteins and oxidative stress markers were evaluated by flow cytometry. Proteins related to the biogenesis of miRNAs were quantified by RT-PCR and Western Blot.
Results Expression of selected miRNAs was significantly decreased in neutrophils from SLE and APS patients compared to healthy donors. However, only miR-124a was found significantly reduced in monocytes from SLE and APS patients. No changes were found in lymphocytes. The expression of those miRNAs negatively correlated with autoimmunity-related parameters (anti-dsDNA and aCL-IgG), disease activity (SLEDAI), inflammation (IL-2, -6, -8 and MCP-1) and oxidative stress (peroxides). Low levels of specific miRNAs in neutrophils and monocytes from both SLE and APS were found further associated with thrombotic events and pathological carotid intima media thickness. This selective decrease miRNA expression was related to a significant reduction in the expression of miRNAs biogenesis genes (Xportin-5, Drosha, Dicer, Ago-1 and Ago-2) in neutrophils from APS and SLE patients compared to healthy donors. In vitro treatment of healthy monocytes with purified antiocardiolipin antibodies from APS patients caused a significant decrease in the levels of miR-124a. Notably, when this miRNA was transfected into monocytic THP-1 cells a significant decrease (∼30%) in MCP-1, STAT3 and p38 expression was observed, pointing at these proteins as potential targets of miR-124a.
Conclusions 1. Decreased expression of a number of miRNAs in monocytes and neutrophils from APS and SLE patients correlates with autoimmunity, inflammation, thrombosis and oxidative stress and atherothrombotic markers. 2. A down-regulation of miRNA processing might explain the low expression of evaluated miRNAs in APS and SLE neutrophils. 3. Antiocardiolipin antibodies directly regulate miR-124a expression, which is directly involved in the proatherosclerotic profile of APS and SLE patients.
Acknowledgements Supported by: P08-CVI-04234, CTS-7940, PI12/01511, PI11/00566, Spanish Rheumatology Society
Disclosure of Interest : None declared
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