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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(11): 1932-1942
DOI: 10.1055/a-1914-2094
Atherosclerosis and Ischaemic Disease

Beta-Secretase-1 Antisense RNA Is Associated with Vascular Ageing and Atherosclerotic Cardiovascular Disease

Authors

  • Dimitrios Bampatsias   *

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Ioannis Mavroeidis   *

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Simon Tual-Chalot   *

    2   Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom

  • Nikolaos I. Vlachogiannis

    2   Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom

  • Francesca Bonini

    3   Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany

  • Marco Sachse

    3   Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany

  • Georgios Mavraganis

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Alexia Mareti

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Chrysoula Kritsioti

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Ageliki Laina

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Dimitrios Delialis

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Giorgia Ciliberti

    3   Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany

  • Kateryna Sopova

    2   Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom

  • Aikaterini Gatsiou

    2   Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom

  • Fabio Martelli

    4   Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Milan, Italy

  • Georgios Georgiopoulos

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

  • Konstantinos Stellos   **

    2   Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom
    3   Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
    5   German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Mannheim, Germany
    6   Department of Cardiology, University Hospital Mannheim, Heidelberg University, Manheim, Germany

  • Kimon Stamatelopoulos   **

    1   Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
    2   Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom

Funding This work was supported by a grant from the German Research Foundation DFG (SFB834 B12, project number 75732319) to K. Stellos. K. Stellos was also supported by a European Research Council (ERC) grant under the European Union's Horizon 2020 Research and Innovation Programme (MODVASC, grant agreement No. 759248). K. Stamatelopoulos was supported by institutional funding. F.M. was supported by the Italian Ministry of Health (“Ricerca Corrente” and RF-2019-12368521), EU COVIRNA # 101016072, Telethon-Italy n. GGP19035, AFM-Telethon n. 23054.
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Graphical Abstract

Abstract

Background The noncoding antisense transcript for β-secretase-1 (BACE1-AS) is a long noncoding RNA with a pivotal role in the regulation of amyloid-β (Aβ). We aimed to explore the clinical value of BACE1-AS expression in atherosclerotic cardiovascular disease (ASCVD).

Methods Expression of BACE1-AS and its target, β-secretase 1 (BACE1) mRNA, was measured in peripheral blood mononuclear cells derived from 434 individuals (259 without established ASCVD [non-CVD], 90 with stable coronary artery disease [CAD], and 85 with acute coronary syndrome). Intima-media thickness and atheromatous plaques evaluated by ultrasonography, as well as arterial wave reflections and pulse wave velocity, were measured as markers of subclinical ASCVD. Patients were followed for a median of 52 months for major adverse cardiovascular events (MACE).

Results In the cross-sectional arm, BACE1-AS expression correlated with BACE1 expression (r = 0.396, p < 0.001) and marginally with Aβ1–40 levels in plasma (r = 0.141, p = 0.008). Higher BACE1-AS was associated with higher estimated CVD risk assessed by HeartScore for non-CVD subjects and by European Society of Cardiology clinical criteria for the total population (p < 0.05 for both). BACE1-AS was associated with higher prevalence of CAD (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.37–2.5), multivessel CAD (OR = 1.36, 95% CI: 1.06–1.75), and with higher number of diseased vascular beds (OR = 1.31, 95% CI: 1.07–1.61, for multiple diseased vascular beds) after multivariable adjustment for traditional cardiovascular risk factors. In the prospective arm, BACE1-AS was an independent predictor of MACE in high cardiovascular risk patients (adjusted hazard ratio = 1.86 per ascending tertile, 95% CI: 1.011–3.43, p = 0.046).

Conclusion BACE1-AS is associated with the incidence and severity of ASCVD.

Keywords

beta-secretase-1 antisense RNA - long noncoding RNA - atherosclerosis - cardiovascular disease - amyloid-β

Note

The graphical abstract was created using templates from Servier Medical Art (smart.servier.com).


Author Contributions

D.B., I.M., S.T-.C. and K. Stamatelopoulos contributed to writing of the manuscript. N.I.V., S.T-.C., M.S., K. Sopova, and A.G. performed RNA analysis. G.G. and K. Stamatelopoulos did the statistical analyses. G.M., A.M., C.K., A.L., and D.D. were involved in participants' recruitment and data collection. F.B., K. Stellos, K. Stamatelopoulos, and F.M. conceptualized the study and proofread the manuscript. K. Stellos and K. Stamatelopoulos coordinated the study.


* Equal first author contribution.


** Equal senior author contribution.


Supplementary Material



Publication History

Received: 17 March 2022

Accepted: 05 July 2022

Accepted Manuscript online:
01 August 2022

Article published online:
27 September 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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