Journal Article

Human Dopamine β-Hydroxylase Promoter Variant Alters Transcription in Chromaffin Cells, Enzyme Secretion, and Blood Pressure

Yuqing Chen, Kuixing Zhang, Gen Wen, Fangwen Rao, Amber P. Sanchez, Lei Wang, Juan L. Rodriguez-Flores, Manjula Mahata, Sushil K. Mahata, Jill Waalen, Michael G. Ziegler, Bruce A. Hamilton and Daniel T. O'Connor

in American Journal of Hypertension

Published on behalf of American Journal of Hypertension, Ltd.

Volume 24, issue 1, pages 24-32
Published in print January 2011 | ISSN: 0895-7061
Published online January 2011 | e-ISSN: 1941-7225 | DOI: http://dx.doi.org/10.1038/ajh.2010.186
Human Dopamine β-Hydroxylase Promoter Variant Alters Transcription in Chromaffin Cells, Enzyme Secretion, and Blood Pressure

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  • Neuroendocrinology and Autonomic Nervous System
  • Biochemistry
  • Endocrinology and Diabetes

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Background

Dopamine β-hydroxylase (DBH) plays an indispensable role in catecholamine synthesis by converting dopamine into norepinephrine. Here, we characterized a DBH promoter polymorphism (C-2073T; rs1989787; minor allele frequency ∼16%) that influences not only gene transcription but also enzyme secretion and blood pressure (BP) in vivo.

Methods

Plasma DBH activity was measured spectrophotometrically. DBH genetic effects on BP were tested in subjects with the most extreme BP values in a large primary care population. Functional effects of promoter variants were studied by site-directed mutagenesis in DBH promoter haplotype/luciferase reporter plasmids transfected into chromaffin cells. Sequence motifs were predicted from position weight matrices, and endogenous transcription factor binding was probed by Chromatin ImmunoPrecipitation (ChIP).

Results

The T-allele of common promoter variant C-2073T was contained in a promoter haplotype that associated with plasma DBH activity, a trait also predicted by that variant itself. Promoter haplotypes including C-2073T predicted BP in the population, and the effect was also referable to C-2073T itself. Computationally, C-2073 disrupted a predicted match for transcription factor c-FOS. Site-directed mutagenesis at C-2073T altered not only basal promoter activity, but also transactivation by c-FOS, as well as the chromaffin cell secretory stimuli nicotine or pituitary adenylate cyclase-activating polypeptide (PACAP). Endogenous c-FOS bound to the motif in chromatin.

Conclusion

These results suggest that DBH promoter variant C-2073T is functional in vivo: this promoter variant seems to initiate a cascade of transcriptional and biochemical changes including augmented DBH secretion, eventuating in elevation of basal BP, and hence cardiovascular risk. The observations suggest new strategies for probing the pathophysiology, risk, and treatment of hypertension.

American Journal of Hypertension, advance online publication 2 September 2010; doi:10.1038/ajh.2010.186

Keywords: blood pressure; dopamine β-hydroxylase; hypertension; polymorphism

Journal Article.  4715 words.  Illustrated.

Subjects: Neuroendocrinology and Autonomic Nervous System ; Biochemistry ; Endocrinology and Diabetes

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