Περίληψη:
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. © 2021 Elsevier B.V.
Συγγραφείς:
Gatsiou, A.
Georgiopoulos, G.
Vlachogiannis, N.I.
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, A.M.
Stamatelopoulos, K.
Dimmeler, S.
Stellos, K.
Λέξεις-κλειδιά:
activating transcription factor 1; aldosterone antagonist; angiotensin receptor antagonist; beta adrenergic receptor blocking agent; beta catenin; hydroxymethylglutaryl coenzyme A reductase inhibitor; microRNA; microRNA 34a; microRNA 34b; microRNA 34c; Notch2 receptor; protein Jagged 1; sirtuin 1; unclassified drug; microRNA; sirtuin 1, adult; aging; animal cell; animal experiment; animal model; animal tissue; arterial stiffness; Article; atherosclerosis; atherosclerotic plaque; cardiovascular risk; cohort analysis; controlled study; coronary artery; coronary artery disease; female; gene expression level; human; human cell; major clinical study; male; middle aged; mouse; nonhuman; peripheral blood mononuclear cell; priority journal; aging; atherosclerosis; mononuclear cell, Aging; Atherosclerosis; Humans; Leukocytes, Mononuclear; MicroRNAs; Sirtuin 1
