title: Inhibition of miR-154 Protects Against Cardiac Dysfunction and Fibrosis in a Mouse Model of Pressure Overload.
abstract: Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, 3086, Australia.
authors.forename: Sally S
authors.initials: SS
authors.lastname: Nguyen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Monash University, Clayton, 3800, Australia.
authors.forename: Yow Keat
authors.initials: YK
authors.lastname: Tham
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Jenny Y Y
authors.initials: JY
authors.lastname: Ooi
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Patterson
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, 3086, Australia.
authors.forename: Colleen J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Asbestos Diseases Research Institute, Concorde Hospital, 2139, Australia.|Ramaciotti Centre for Genomics and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, 2052, Australia.
authors.forename: Ruby C Y
authors.initials: RC
authors.lastname: Lin
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Monash University, Clayton, 3800, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Monash University, Clayton, 3800, Australia.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004452:Echocardiography; D006973:Hypertension / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000235:genetics*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics*
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; C000598889:MIRN154 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; C477371:locked nucleic acid; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor