title: Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production.
abstract: Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Wu
authors.affiliation: Cardiology Division, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Arora
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Obiajulu
authors.initials: O
authors.lastname: Agha
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Liam A
authors.initials: LA
authors.lastname: Hurst
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Allen
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Nathan
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
authors.forename: Dongjian
authors.initials: D
authors.lastname: Hu
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Pawina
authors.initials: P
authors.lastname: Jiramongkolchai
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Cardiology, Clinical Sciences, Lund University, and Department of Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden.
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.affiliation: Department of Internal Medicine, Clinical Sciences, Lund University, and Skåne University Hospital, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Sander
authors.initials: S
authors.lastname: Trenson
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Janssens
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Domian
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA EBUYS@mgh.harvard.edu dbloch@partners.org.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA EBUYS@mgh.harvard.edu dbloch@partners.org.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
authors.affiliation: Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
mesh_terms: D000483:Alleles; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D014644:Genetic Variation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy
chemical_list: C588223:MIRN105 microRNA, human; C524942:MIRN155 microRNA, human; C555677:MIRN425 microRNA, human; D035683:MicroRNAs; C472955:NPPA protein, human; D009320:Atrial Natriuretic Factor