Characterization of Antiphospholipid Syndrome Atherothrombotic Risk by Unsupervised Integrated Transcriptomic Analyses.

Journal: Arteriosclerosis, thrombosis, and vascular biology
PMID: 33356391

Abstract

OBJECTIVE: Our aim was to characterize distinctive clinical antiphospholipid syndrome phenotypes and identify novel microRNA (miRNA)-mRNA-intracellular signaling regulatory networks in monocytes linked to cardiovascular disease. Approach and Results: Microarray analysis in antiphospholipid syndrome monocytes revealed 547 differentially expressed genes, mainly involved in inflammatory, cardiovascular, and reproductive disorders. Besides, this approach identified several genes related to inflammatory, renal, and dermatologic diseases. Functional analyses further demonstrated phosphorylation of intracellular kinases related to thrombosis and immune-mediated chronic inflammation. miRNA profiling showed altered expression of 22 miRNAs, enriched in pathways related to immune functions, cardiovascular disease, and autoimmune-associated pathologies. Unbiased integrated mRNA-miRNA analysis identified a signature of 9 miRNAs as potential modulators of 17 interconnected genes related to cardiovascular disease. The altered expression of that miRNA-mRNA signature was proven to be stable along time and distinctive of nonautoimmune thrombotic patients. Transfection studies and luciferase assays established the relationship between specific miRNAs and their identified target genes and proteins, along with their involvement in the regulation of monocytes procoagulant activity and cell adhesion. Correlation analyses showed relationship among altered miRNAs and their interconnected genes with aPL (antiphospholipid antibodies)-titers, along with microvascular endothelial dysfunction. In vitro studies demonstrated modulation in healthy monocytes by IgG-aPLs of several genes/miRNAs, which further intermediated downstream effects on endothelial function. The identified transcriptomic signature allowed the unsupervised division of three clusters of patients with antiphospholipid syndrome showing distinctive clinical profiles, mainly associated with their prothrombotic risk (thrombosis, autoantibody profile, cardiovascular risk factors, and atherosclerosis).

Authors

  • Laura Pérez-Sánchez
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Alejandra M Patiño-Trives
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • M Ángeles Aguirre-Zamorano
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • María Luque-Tévar
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • M Carmen Ábalos-Aguilera
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Iván Arias-de la Rosa
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Pedro Seguí
    Radiology Service (P.S.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Francisco Velasco-Gimena
    Haematology Service (F.V.-G.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Nuria Barbarroja
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Alejandro Escudero-Contreras
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Eduardo Collantes-Estévez
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.
  • Carlos Pérez-Sánchez
    Deparment of Medicine, University of Cambridge, School of Clinical Medicine, Addenbroke's Hospital, Cambridge Institute for Medical Research, United Kingdom (C.P.-S.).
  • Chary López-Pedrera
    Rheumatology Service (L.P.-S., A.M.P.-T., M.A.A.-Z., M.L.-T., M.C.A.-A., I.A.-d.l.R., N.B., A.E.-C., E.C.-E., C.L.-P.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.

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