Document Detail


Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat.
MedLine Citation:
PMID:  20378607     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Understanding catecholamine metabolism is crucial for elucidating the pathogenesis of hereditary hypertension. Here we integrated transcriptional and biochemical profiling with physiologic quantitative trait locus (eQTL and pQTL) mapping in adrenal glands of the HXB/BXH recombinant inbred (RI) strains, derived from the spontaneously hypertensive rat (SHR) and normotensive Brown Norway (BN.Lx). We found simultaneous down-regulation of five heritable transcripts in the catecholaminergic pathway in young (6 weeks) SHRs. We identified cis-acting eQTLs for Dbh, Pnmt (catecholamine biosynthesis) and Vamp1 (catecholamine secretion); enzymatic activities of Dbh and Pnmt paralleled transcripts, with pQTLs for activities mirroring eQTLs. We also detected trans-regulated expression of Vmat1 and Chga (both involved in catecholamine storage), with co-localization of these trans-eQTLs to the Pnmt locus. Pnmt re-sequencing revealed promoter polymorphisms that result in decreased response of the transfected SHR promoter to glucocorticoid, compared with BN.Lx. Of physiological pertinence, Dbh activity negatively correlated with systolic blood pressure in RI strains, whereas Pnmt activity was negatively correlated with heart rate. The finding of such cis- and trans-QTLs at an age before the onset of frank hypertension suggests that these heritable changes in biosynthetic enzyme expression represent primary genetic mechanisms for regulation of catecholamine action and blood pressure control in this widely studied model of hypertension.
Authors:
M L Jirout; R S Friese; N R Mahapatra; M Mahata; L Taupenot; S K Mahata; V Kren; V Zídek; J Fischer; H Maatz; M G Ziegler; M Pravenec; N Hubner; T J Aitman; N J Schork; D T O'Connor
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-04-08
Journal Detail:
Title:  Human molecular genetics     Volume:  19     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-11     Completed Date:  2010-09-20     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  2567-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adrenal Glands / physiology
Animals
Catecholamines / biosynthesis,  chemistry,  genetics*
Disease Models, Animal
Gene Expression Regulation*
Heart Rate
Hypertension* / genetics,  metabolism
Quantitative Trait Loci / genetics*
Rats
Rats, Inbred BN
Rats, Inbred SHR
Grant Support
ID/Acronym/Agency:
MC_U120061454//Medical Research Council; P01 HL058120/HL/NHLBI NIH HHS; P01 HL058120-10/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Catecholamines
Comments/Corrections

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