title: MicroRNA-539 is up-regulated in failing heart, and suppresses O-GlcNAcase expression.
abstract: Derangements in metabolism and related signaling pathways characterize the failing heart. One such signal, O-linked β-N-acetylglucosamine (O-GlcNAc), is an essential post-translational modification regulated by two enzymes, O-GlcNAc transferase and O-GlcNAcase (OGA), which modulate the function of many nuclear and cytoplasmic proteins. We recently reported reduced OGA expression in the failing heart, which is consistent with the pro-adaptive role of increased O-GlcNAcylation during heart failure; however, molecular mechanisms regulating these enzymes during heart failure remain unknown. Using miRNA microarray analysis, we observed acute and chronic changes in expression of several miRNAs. Here, we focused on miR-539 because it was predicted to target OGA mRNA. Indeed, co-transfection of the OGA-3'UTR containing reporter plasmid and miR-539 overexpression plasmid significantly reduced reporter activity. Overexpression of miR-539 in neonatal rat cardiomyocytes significantly suppressed OGA expression and consequently increased O-GlcNAcylation; conversely, the miR-539 inhibitor rescued OGA protein expression and restored O-GlcNAcylation. In conclusion, this work identifies the first target of miR-539 in the heart and the first miRNA that regulates OGA. Manipulation of miR-539 may represent a novel therapeutic target in the treatment of heart failure and other metabolic diseases.
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Muthusamy
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: DeMartino
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Watson
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Brittian
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Zafir
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Sujith
authors.initials: S
authors.lastname: Dassanayaka
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Kyung U
authors.initials: KU
authors.lastname: Hong
authors.affiliation: From the Institute of Molecular Cardiology, and, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202 Steven.P.Jones@Louisville.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D006031:Glycosylation; D057809:HEK293 Cells; D006333:Heart Failure / Q000235:genetics*; D006334:Heart Function Tests; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000235:genetics*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D010100:Oxygen
keywords: Heart Failure; Hexosamine; Metabolism; MicroRNA (miRNA); O-GlcNAcylation; Post-transcriptional Regulation