title: Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy.
abstract: Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; julie.mcmullen@bakeridi.edu.au bianca.bernardo@bakeridi.edu.au.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Human Biosciences, La Trobe University, Bundoora, Victoria, Australia;
authors.forename: Sally S
authors.initials: SS
authors.lastname: Nguyen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Esther J H
authors.initials: EJ
authors.lastname: Boey
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Yow Keat
authors.initials: YK
authors.lastname: Tham
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Jenny Y Y
authors.initials: JY
authors.lastname: Ooi
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia; and.
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia; and.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Igoor
authors.affiliation: Department of Human Biosciences, La Trobe University, Bundoora, Victoria, Australia;
authors.forename: Colleen J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: Ramaciotti Centre for Genomics and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Ruby C Y
authors.initials: RC
authors.lastname: Lin
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; julie.mcmullen@bakeridi.edu.au bianca.bernardo@bakeridi.edu.au.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D002478:Cells, Cultured; D020868:Gene Silencing; D006321:Heart / Q000503:physiopathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C000594930:MIRN652 microRNA, mouse; D035683:MicroRNAs
keywords: LNA-therapeutics; heart failure; microRNAs; pressure overload