New Biomarkers for Atherothrombosis in Antiphospholipid Syndrome: Genomics and Epigenetics Approaches

Abstract

Antiphospholipid Syndrome (APS) is an autoimmune disorder, characterized by pregnancy morbidity and/or a hyper coagulable state involving the venous or the arterial vasculature and associated with antiphospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), anti-beta2-glycoprotein I (anti-ß2GPI), and Lupus anticoagulant (LA). In recent years there have been many advances in the understanding of the molecular basis of vascular involvement in APS. APS is of multifactorial origin and develops in genetically predisposed individuals. The susceptibility is determined by major histocompatibility complex (MHC). Different HLA-DR and HLA-DQ alleles have been reported in association with APS. Moreover, MHC II alleles may determine the autoantibody profile and, as such, the clinical phenotype of this disease. Besides, polymorphisms in genes related to the vascular system are considered relevant factors predisposing to clinical manifestations. Antiphospholipid antibodies (aPL) induce genomic and epigenetic alterations that support a pro- thrombotic state. Thus, a specific gene profile has been identified in monocytes from APS patients -related to aPL titres in vivo and promoted in vitro by aPL- explaining their cardiovascular involvement. Regarding epigenetic approaches, we previously recognized two miRNAs (miR-19b/miR-20a) as potential modulators of tissue factor, the main receptor involved in thrombosis development in APS. aPLs can further promote changes in the expression of miRNA biogenesis proteins in leukocytes of APS patients, which are translated into an altered miRNA profile and, consequently, in the altered expression of their protein targets related to thrombosis and atherosclerosis. MicroRNAs are further released into the circulation, acting as intercellular communicators. Accordingly, a specific signature of circulating miRNAs has been recently identified in APS patients as potential biomarkers of clinical features. Genomics and epigenetic biomarkers might also serve as indices for disease progression, clinical pharmacology, or safety, so that they might be used to individually predict disease outcome and guide therapeutic decisions. In that way, in the setting of a clinical trial, novel and specific microRNA–mRNA regulatory networks in APS, modified by effect of Ubiquinol treatment, have been identified. In this review, current and previous studies analyzing genomic/epigenetic changes related to the clinical profile of APS patients, and their modulation by effect of specific therapies, are discussed.

circRNA‑0006896‑miR1264‑DNMT1 axis plays an important role in carotid plaque destabilization by regulating the behavior of endothelial cells in atherosclerosis

“…Previous studies have been conducted to identify therapeutic targets for UA, most of which have been limited to protein-coding genes, miRNAs and lncRNAs (32)(33)(34)(35). Recently, circRNAs have attracted attention as new diagnostic markers for diseases, including cancer.…”

The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

“…Neuroprotective effect by preconditioning through suppression of cytotoxic TNFα, increasing IRFs and production of type I interferons [78,79] Induction and evolution of atherosclerosis through NF-κB pathway that produce inflammation [78,79] Increasing levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region [82] Activation by Heme product through the MyD88 and TRIF pathways [83] Activated in antiphospholipid syndrome [80] TLR7…”

“…Neuroprotective effect by preconditioning through suppression of cytotoxic TNFα, increasing IRFs, and production of type I interferons [20] -Deletion is associated with larger venous thrombosis and increased leukocyte infiltration [80] AIS acute ischemic stroke, APS antiphospholipid syndrome, ICH intracerebral hemorrhage, CVD cerebral vascular disease, CVST cerebral venous sinus thrombosis, SAH subarachnoid hemorrhage, SD spreading depolarization, TNF tissue necrosis factor, IFNA interferon-α/β receptor, TLR Toll-like receptor the infarct volume in animal experimental models [20]. Systemic administration of low doses of lipopolysaccharide (LPS), a TLR4 ligand, a cell wall component of gram-negative bacteria, to hypertensive rats caused tolerance to subsequent brain ischemia induced by middle cerebral artery occlusion [96].…”

“…Application of TLR9 agonist was associated with smaller venous thrombosis in this model. It has been shown that the TLR pathway mainly through TLR2 and TLR4 is activated in patients with antiphospholipid syndrome, suggesting a biomarker role of TLRs in this syndrome [80]. Moreover, a significant rise in the gene expression of TLR2 and TLR4 was observed in peripheral mononuclear cells that mediate antiphospholipid antibodies induced vascular abnormalities.…”

Current Promising Biomarkers and Methods in the Diagnostics of Antiphospholipid Syndrome: A Review

“…The main target of the aPLs is binding to the phospholipid membranes of platelets with their subsequent activation. However, they also bind to endothelia, monocytes, and neutrophils with a procoagulation effect [2,3]. Antiphospholipid antibodies also interfere with the activation of the complement.…”