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

Gatsiou, Aikaterini; Georgiopoulos, Georgios; Vlachogiannis, Nikolaos I.; Pfisterer, Larissa; Fischer, Ariane; Sachse, Marco; Laina, Ageliki; Bonini, Francesca; Delialis, Dimitrios; Tual-Chalot, Simon; Zormpas, Eleftherios; Achangwa, Rawlings; Jiang, Longchang; Kontogiannis, Christos; Patras, Raphael; Hermeking, Heiko; Zeiher, Andreas M.; Stamatelopoulos, Kimon; Dimmeler, Stefanie und Stellos, Konstantinos (2021): Additive contribution of microRNA-34a/b/c to human arterial ageing and atherosclerosis. In: Atherosclerosis, Bd. 327: S. 49-58

Abstract

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 (PSPRINGER NATUREs) 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-9150
• Sprache: Englisch