Background/Purpose: 1) To identify and characterize microRNAs linked to thrombosis and atherosclerosis development in APS; 2) To assess the effects of antiphospholipid antibodies in that epigenetic process.

Methods: Six microRNAs proven to be involved in atherothrombosis development (miR-124-a, -125a, -125b, -146a, -155, and -222), were quantified in purified leukocytes from 23 APS and 56 healthy donors. In parallel, pro-inflammatory and prothrombotic proteins and oxidative stress markers were evaluated at both, plasma and cellular levels. Proteins related to the biogenesis of miRNAs (Drosha, Dicer, Ago-1, Ago-2 and Xpo-5) were quantified by RT-PCR and Western blot. The clinical cardiovascular disease (CVD) profile was further recorded in APS patients. In vitro experiments were performed in endothelial cells (ECs), monocytes, and neutrophils, which were treated with anti-phospholipid antibodies of IgG isotype (aPL-IgG) purified from APS patients’ serum, or with IgG from healthy donors (IgG-NHS).

Results: Levels of microRNAs in neutrophils were lower in APS than in healthy donors. Accordingly, gene and protein expression of miRNA biogenesis-related molecules were reduced. In monocytes, miR124a and -125a were low, while miR-146a and miR-155 appeared elevated. The expression levels of some miRNAs differentially expressed in neutrophils and monocytes significantly correlated with parameters related to autoimmunity, thrombosis, inflammation and oxidative stress. Association studies showed that the occurrence of thrombotic events and the presence of a pathological increase in the CIMT were linked to altered levels of a number of miRNAs in neutrophils and monocytes, as well as with low levels of proteins related to miRNA biogenesis. An additional control group, including 20 patients with thrombosis but without aPL was evaluated. Thrombotic patients displayed a specific profile of miRNA expression that differed from that of APS patients, thus indicating a differential mode of regulation and activity. In vitro treatment of neutrophils, monocytes, and ECs with aPL-IgG antibodies deregulated microRNAs expression, and decreased miRNA biogenesis-related proteins. Accordingly, aPL-IgG antibodies induced upregulation of MCP-1, TF and VCAM-1, and downregulation of eNOS, relevant markers of endothelial dysfunction, and potential targets of the miRNAs evaluated. Monocyte transfections with pre-miR-124a and/or -125a validated the data obtained, causing reduction in atherothrombosis-related target molecules.

Conclusion:  1. Specific miRNAs might act as modulators of atherothrombosis in APS patients. 2. Antiphospholipid antibodies regulate CVD in APS, at least partially, by regulating the biogenesis and the expression of miRNAs. Funded by CTS7940, PI15/01333.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/micrornas-as-potential-modulators-of-atherothrombosis-in-antiphospholipid-syndrome/