title: 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.
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.
authors.affiliation: Department of Bioengineering, VA San Diego Healthcare System, University of California at San Diego, CA 92093, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Friese
authors.forename: Angelina E
authors.initials: AE
authors.lastname: Altshuler
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: Jose Pablo
authors.initials: JP
authors.lastname: Miramontes-Gonzalez
authors.forename: C Makena
authors.initials: CM
authors.lastname: Hightower
authors.forename: Martin L
authors.initials: ML
authors.lastname: Jirout
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.forename: Nitish R
authors.initials: NR
authors.lastname: Mahapatra
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.forename: Mo
authors.initials: M
authors.lastname: Cale
authors.forename: Sucheta M
authors.initials: SM
authors.lastname: Vaingankar
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Maïté
authors.initials: M
authors.lastname: Courel
authors.forename: Laurent
authors.initials: L
authors.lastname: Taupenot
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D020413:3' Untranslated Regions; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D001933:Brain Stem / Q000378:metabolism; D045744:Cell Line, Tumor; D053379:Chromogranin A / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016716:PC12 Cells; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D016415:Sequence Alignment; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; C506150:CHGA protein, human; D053379:Chromogranin A; D004268:DNA-Binding Proteins; C580892:MIRN22 microRNA, rat; D035683:MicroRNAs; C506153:chromogranin A, rat