title: Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function.
abstract: MicroRNAs are dysregulated in a setting of heart disease and have emerged as promising therapeutic targets. MicroRNA-34 family members (miR-34a, -34b, and -34c) are up-regulated in the heart in response to stress. In this study, we assessed whether inhibition of the miR-34 family using an s.c.-delivered seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiR (LNA-antimiR-34) can provide therapeutic benefit in mice with preexisting pathological cardiac remodeling and dysfunction due to myocardial infarction (MI) or pressure overload via transverse aortic constriction (TAC). An additional cohort of mice subjected to MI was given LNA-antimiR-34a (15-mer) to inhibit miR-34a alone as a comparison for LNA-antimiR-34. LNA-antimiR-34 (8-mer) efficiently silenced all three miR-34 family members in both cardiac stress models and attenuated cardiac remodeling and atrial enlargement. In contrast, inhibition of miR-34a alone with LNA-antimiR-34a (15-mer) provided no benefit in the MI model. In mice subjected to pressure overload, LNA-antimiR-34 improved systolic function and attenuated lung congestion, associated with reduced cardiac fibrosis, increased angiogenesis, increased Akt activity, decreased atrial natriuretic peptide gene expression, and maintenance of sarcoplasmic reticulum Ca(2+) ATPase gene expression. Improved outcome in LNA-antimiR-34-treated MI and TAC mice was accompanied by up-regulation of several direct miR-34 targets, including vascular endothelial growth factors, vinculin, protein O-fucosyltranferase 1, Notch1, and semaphorin 4B. Our results provide evidence that silencing of the entire miR-34 family can protect the heart against pathological cardiac remodeling and improve function. Furthermore, these data underscore the utility of seed-targeting 8-mer LNA-antimiRs in the development of new therapeutic approaches for pharmacologic inhibition of disease-implicated miRNA seed families.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC 8008,  Australia.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Esther J H
authors.initials: EJ
authors.lastname: Boey
authors.forename: Yow Keat
authors.initials: YK
authors.lastname: Tham
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.forename: Susanna
authors.initials: S
authors.lastname: Obad
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Ruby C Y
authors.initials: RC
authors.lastname: Lin
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism; D005647:Fucosyltransferases / Q000378:metabolism; D006334:Heart Function Tests; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D009841:Oligonucleotides / Q000737:chemistry; D051560:Proto-Oncogene Proteins c-bcl-6; D039961:Semaphorins / Q000378:metabolism; D015854:Up-Regulation; D020257:Ventricular Remodeling; D016596:Vinculin / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D051560:Proto-Oncogene Proteins c-bcl-6; D039961:Semaphorins; C477371:locked nucleic acid; C558170:semaphorin 4B, mouse; D016596:Vinculin; D004247:DNA; D005647:Fucosyltransferases; C539426:Pofut1 protein, mouse