Characterization of Antiphospholipid Syndrome Atherothrombotic Risk by Unsupervised Integrated Transcriptomic Analyses

Author:

Pérez-Sánchez Laura1,Patiño-Trives Alejandra M.1,Aguirre-Zamorano M. Ángeles1ORCID,Luque-Tévar María1,Ábalos-Aguilera M. Carmen1,Arias-de la Rosa Iván1,Seguí Pedro2,Velasco-Gimena Francisco3,Barbarroja Nuria14ORCID,Escudero-Contreras Alejandro1,Collantes-Estévez Eduardo1ORCID,Pérez-Sánchez Carlos5,López-Pedrera Chary1ORCID

Affiliation:

1. 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.

2. Radiology Service (P.S.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.

3. Haematology Service (F.V.-G.), Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba, Spain.

4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain (N.B.).

5. Deparment of Medicine, University of Cambridge, School of Clinical Medicine, Addenbroke’s Hospital, Cambridge Institute for Medical Research, United Kingdom (C.P.-S.).

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). Conclusions: Extensive molecular profiling of monocytes in patients with primary antiphospholipid syndrome might help to identify distinctive clinical phenotypes, thus enabling new patients’ tailored treatments.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

Cited by 14 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3