MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension
Open Access
- 13 May 2013
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 22 (18), 3624-3640
- https://doi.org/10.1093/hmg/ddt213
Abstract
Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (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.This publication has 73 references indexed in Scilit:
- Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAsNature Structural & Molecular Biology, 2011
- microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicityBritish Journal of Cancer, 2010
- Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive ratHuman Molecular Genetics, 2010
- Effects of chromogranin A deficiency and excess in vivo: biphasic blood pressure and catecholamine responsesJournal of Hypertension, 2010
- Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressureJournal of Hypertension, 2010
- Neuropeptide Y1Receptor NPY1R: Discovery of Naturally Occurring Human Genetic Variants Governing Gene Expression In Cella as Well as Pleiotropic Effects on Autonomic Activity and Blood Pressure In VivoJournal of the American College of Cardiology, 2009
- Naturally Occurring Human Genetic Variation in the 3′-Untranslated Region of the Secretory Protein Chromogranin A Is Associated With Autonomic Blood Pressure Regulation and Hypertension in a Sex-Dependent FashionJournal of the American College of Cardiology, 2008
- Common genetic variants in the chromogranin A promoter alter autonomic activity and blood pressureKidney International, 2008
- The Human Genome Browser at UCSCGenome Research, 2002
- Predicting Coiled Coils from Protein SequencesScience, 1991