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Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat

Item Type:Article
Title:Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat
Creators Name:Jirout, M.L. and Friese, R.S. and Mahapatra, N.R. and Mahata, M. and Taupenot, L. and Mahata, S.K. and Kren, V. and Zidek, V. and Fischer, J. and Maatz, H. and Ziegler, M.G. and Pravenec, M. and Huebner, N. and Aitman, T.J. and Schork, N.J. and O'Connor, D.T.
Abstract: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) SHR. 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 to BN.Lx. Of physiological pertinence, Dbh activity negatively correlated with systolic blood pressure in RI strains, while 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.
Keywords:Adrenal Glands, Catecholamines, Animal Disease Models, Gene Expression Regulation, Heart Rate, Hypertension, Quantitative Trait Loci, Animals, Rats
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:19
Number:13
Page Range:2567-2580
Date:1 July 2010
Official Publication:https://doi.org/10.1093/hmg/ddq135
PubMed:View item in PubMed

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