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Additive contribution of microRNA-34a/b/c to human arterial ageing and atherosclerosis

Lookup NU author(s): Dr Aikaterini GatsiouORCiD, Dr Georgios Georgiopoulos, Dr Nikolaos VlachogiannisORCiD, Dr Simon Tual-ChalotORCiD, Lefteris Zormpas, Professor Kimon Stamatelopoulos, Professor Konstantinos StellosORCiD

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Abstract

© 2021 Elsevier B.V.Background and aims: Preclinical data suggest that the ageing-induced miR-34a regulates vascular senescence. Herein we sought to assess whether the miR-34 family members miR-34a, miR-34b and miR-34c are involved in human arterial disease. Methods: Expression levels of miR-34a/b/c were quantified by TaqMan assay in peripheral blood mononuclear cells (PBMCs) derived from a consecutive cohort of 221 subjects who underwent cardiovascular risk assessment and thorough vascular examination for aortic stiffness and extent of arterial atherosclerosis. Results: High miR-34a was independently associated with the presence of CAD [OR (95%C.I.): 3.87 (1.56–9.56); p = 0.003] and high miR-34c with the number of diseased arterial beds [OR (95%C.I.): 1.88 (1.034–3.41); p = 0.038], while concurrent high expression of miR-34-a/c or all three miR-34a/b/c was associated with aortic stiffening (miR-34a/c: p = 0.022; miR-34a/b/c: p = 0.041) and with the extent of atherosclerosis [OR (95%C.I.) for number of coronary arteries [miR-34a/c: 3.29 (1.085–9.95); miR-34a/b/c: 6.06 (1.74–21.2)] and number of diseased arterial beds [miR-34a/c: 3.51 (1.45–8.52); miR-34a/b/c: 2.89 (1.05–7.92)] after controlling for possible confounders (p < 0.05 for all). Mechanistically, the increased levels of miR-34a or miR-34c were inversely associated with expression of SIRT1 or JAG1, NOTCH2, CTNNB1 and ATF1, respectively. The association of miR-34a/c or miR-34a/b/c with CAD was mainly mediated through SIRT1 and to a lesser extent through JAG1 as revealed by generalized structural equation modeling. Leukocyte-specific ablation of miR-34a/b/c ameliorates atherosclerotic plaque development and increases Sirt1 and Jag1 expression in an atherosclerosis mouse model confirming the human findings. Conclusions: The present study reveals the clinical significance of the additive role of miR-34a/b/c in vascular ageing and atherosclerotic vascular disease.

Publication metadata

Author(s): Gatsiou A, Georgiopoulos G, Vlachogiannis NI, Pfisterer L, Fischer A, Sachse M, Laina A, Bonini F, Delialis D, Tual-Chalot S, Zormpas E, Achangwa R, Jiang L, Kontogiannis C, Patras R, Hermeking H, Zeiher AM, Stamatelopoulos K, Dimmeler S, Stellos K

Publication type: Article

Publication status: Published

Journal: Atherosclerosis

Year: 2021

Volume: 327

Pages: 49-58

Print publication date: 01/06/2021

Online publication date: 15/05/2021

Acceptance date: 12/05/2021

ISSN (print): 0021-9150

ISSN (electronic): 1879-1484

Publisher: Elsevier Ireland Ltd

URL: https://doi.org/10.1016/j.atherosclerosis.2021.05.005

DOI: 10.1016/j.atherosclerosis.2021.05.005

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