|Human Dopamine beta-Hydroxylase Promoter Variant Alters Transcription in Chromaffin Cells, Enzyme Secretion, and Blood Pressure|
|Chen, Yuqing1,2; Zhang, Kuixing1; Wen, Gen1; Rao, Fangwen1; Sanchez, Amber P.1; Wang, Lei1; Rodriguez-Flores, Juan L.1; Mahata, Manjula1; Mahata, Sushil K.1,3; Waalen, Jill4; Ziegler, Michael G.1; Hamilton, Bruce A.1; O&prime1; Connor, Daniel T.1,3,5,6|
|关键词||Blood Pressure Dopamine Beta-hydroxylase Hypertension Polymorphism|
|刊名||AMERICAN JOURNAL OF HYPERTENSION|
|WOS标题词||Science & Technology|
|类目[WOS]||Peripheral Vascular Disease|
|研究领域[WOS]||Cardiovascular System & Cardiology|
|关键词[WOS]||DEFICIENCY ; NOREPINEPHRINE ; IDENTIFICATION ; POLYMORPHISMS ; MUTATIONS ; PROFILES ; DATABASE ; DISEASE ; JASPAR ; GENE|
Dopamine beta-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 similar to 16%) that influences not only gene transcription but also enzyme secretion and blood pressure (BP) in vivo.
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).
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.
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.
|资助机构||National Institutes of Health, Department of Veterans Affairs ; International Society of Nephrology|
|作者单位||1.Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA|
2.Peking Univ, Hosp 1, Div Renal, Dept Med, Beijing 100871, Peoples R China
3.VA San Diego Healthcare Syst, La Jolla, CA USA
4.Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
5.Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92103 USA
6.Univ Calif San Diego, IGM, San Diego, CA 92103 USA
|Chen, Yuqing,Zhang, Kuixing,Wen, Gen,et al. Human Dopamine beta-Hydroxylase Promoter Variant Alters Transcription in Chromaffin Cells, Enzyme Secretion, and Blood Pressure[J]. AMERICAN JOURNAL OF HYPERTENSION,2011,24(1):24-32.|
|APA||Chen, Yuqing.,Zhang, Kuixing.,Wen, Gen.,Rao, Fangwen.,Sanchez, Amber P..,...&Connor, Daniel T..(2011).Human Dopamine beta-Hydroxylase Promoter Variant Alters Transcription in Chromaffin Cells, Enzyme Secretion, and Blood Pressure.AMERICAN JOURNAL OF HYPERTENSION,24(1),24-32.|
|MLA||Chen, Yuqing,et al."Human Dopamine beta-Hydroxylase Promoter Variant Alters Transcription in Chromaffin Cells, Enzyme Secretion, and Blood Pressure".AMERICAN JOURNAL OF HYPERTENSION 24.1(2011):24-32.|