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MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: Functional andtherapeutic implications forgeneexpressionand the pathogenesis of hypertension
Published in
2013
PMID: 23674521
Volume: 22
   
Issue: 18
Pages: 3624 - 3640
Abstract
Hypertension is acommonhereditary syndromewith unclear pathogenesis. ChromograninA(Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in spontaneously hypertensive rat (SHR) adrenal glands and plasma, but central expression is unexplored. In this report, we measured SHR and Wistar-Kyoto rat (control) Chga expression in central and peripheral nervous systems, and found Chga protein to be decreased in the SHR brainstem, yet increased in the adrenal and the plasma. By re-sequencing, we systematically identified five promoter, two coding and one 3'-untranslated region (3'-UTR) polymorphism at the SHR (versus WKY or BN) Chga locus. Using HXB/BXH recombinant inbred (RI) strain linkage and correlations, we demonstrated genetic determination of Chga expression in SHR, including a cis-quantitative trait loci (QTLs) (i.e. at the Chga locus), and such expression influenced biochemical determinants of blood pressure, including a cascade of catecholamine biosynthetic enzymes, catecholamines themselves and steroids. Luciferase reporter assays demonstrated that the 3'-UTR polymorphism (which disrupts a microRNA miR-22 motif) and promoter polymorphisms altered gene expression consistent with the decline in SHR central Chga expression. Coding region polymorphisms did not account for changes in Chga expression or function. Thus, we hypothesized that the 3'-UTR and promoter mutations lead to dysregulation (diminution) of Chga in brainstem cardiovascular control nuclei, ultimately contributing to the pathogenesis of hypertension in SHR. Accordingly, we demonstrated that in vivo administration of miR-22 antagomir to SHR causes substantial (~18 mmHg) reductions in blood pressure, opening a novel therapeutic avenue for hypertension. © The Author 2013. Published by Oxford University Press. All rights reserved.
About the journal
JournalHuman Molecular Genetics
ISSN09646906
Open AccessYes
Concepts (66)
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    Alanine aminotransferase
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    Alpha amylase pancreas isoenzyme
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    ANTAGOMIR
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    CATECHOLAMINE
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    Chromogranin a
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    Glutamic acid
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    Glutamine
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    INTERFERON REGULATORY FACTOR 1
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    Messenger rna
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    MICRORNA 22
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    TRANSCRIPTION FACTOR E2F1
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    TRANSCRIPTION FACTOR PBX1
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    Transcription factor sox17
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    3' UNTRANSLATED REGION
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    ADRENAL GLAND
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    Animal cell
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    Animal experiment
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    Animal model
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    Animal tissue
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    Article
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    BRAIN STEM
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    Central nervous system
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    Controlled study
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    Correlation analysis
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    Diastolic blood pressure
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    Gene expression
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    Gene mutation
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    Genetic code
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    HEREDITARY HYPERTENSION
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    Human
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    Human cell
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    In vivo study
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    Indel mutation
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    Male
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    Nonhuman
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    Peripheral nervous system
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    Priority journal
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    Promoter region
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    Protein motif
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    QUANTITATIVE TRAIT LOCUS
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    Rat
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    RECOMBINANT INBRED STRAIN
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    Single nucleotide polymorphism
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    Systolic blood pressure
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    3' UNTRANSLATED REGIONS
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    ADRENAL GLANDS
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    Animals
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    BLOOD PRESSURE
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    BRAIN STEM
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    Cell line, tumor
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    Dna-binding proteins
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    Gene expression regulation
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    GENETIC LINKAGE
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    Humans
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    Hypertension
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    Micrornas
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    Pc12 cells
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    POLYMORPHISM, GENETIC
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    Promoter regions, genetic
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    Protein structure, secondary
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    Quantitative trait loci
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    Rats
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    RATS, INBRED SHR
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    RATS, INBRED WKY
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    Sequence alignment
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    Transcription, genetic