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Citations to this article

Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding
Xue Bai, … , Joan M. Taylor, Christopher P. Mack
Xue Bai, … , Joan M. Taylor, Christopher P. Mack
Published January 23, 2017
Citation Information: J Clin Invest. 2017;127(2):670-680. https://doi.org/10.1172/JCI88899.
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Research Article Genetics Vascular biology Article has an altmetric score of 3

Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

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Abstract

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure–associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42’s role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9–mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies.

Authors

Xue Bai, Kevin D. Mangum, Rachel A. Dee, George A. Stouffer, Craig R. Lee, Akinyemi Oni-Orisan, Cam Patterson, Jonathan C. Schisler, Anthony J. Viera, Joan M. Taylor, Christopher P. Mack

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 Total
Citations: 2 2 4 4 5 4 4 1 2 28
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Citations to this article (28)

Title and authors Publication Year
Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling
Kevin D Mangum, Qinmengge Li, Katherine Hartmann, Tyler M Bauer, Sonya J. Wolf, James Shadiow, Jadie Y. Moon, Emily Barrett, Amrita Joshi, Gabriela Saldana de Jimenez, Sabrina A. Rocco, Zara Ahmed, Rachael Bogle, Kylie Boyer, Andrea Obi, Frank M Davis, Lin Chang, Lam Tsoi, Johann Gudjonsson, Scott M. Damrauer, Katherine Gallagher
Journal of Clinical Investigation 2025
Uncovering therapeutic targets for Pre-eclampsia and pregnancy hypertension via multi-tissue data integration
Yao H, Chen J, Wang Y, Li Y, Tang P, Liang M, Jiang Q
BMC Pregnancy and Childbirth 2025
Serum response factor promoting axonal regeneration by activating the Ras–Raf‐Cofilin signaling pathway after the spinal cord injury
Gao L, Zhang C, Zhu Y, Zhang N, Zhang C, Zhou S, Feng G, Huang F, Zhang L
CNS Neuroscience & Therapeutics 2024
Gene editing of angiotensin for blood pressure management
Masi S, Dalpiaz H, Borghi C
International Journal of Cardiology. Cardiovascular Risk and Prevention 2024
Prdm6 promotes a ductus arteriosus-selective gene program in smooth muscle cells that drives ductus arteriosus contractility and closure
Meng Zou, Kevin D Mangum, Justin C Magin, Heidi H Cao, Michael T Yarboro, Elaine L. Shelton, Joan Taylor, Jeff Reese, Terrence Furey, Christopher Mack
JCI Insight 2023
Semaphorin3A Exacerbates Cardiac Microvascular Rarefaction in Pressure Overload‐Induced Heart Disease
Li C, Zhao Y, Li F, Wang Z, Qiu Z, Yang Y, Xiong W, Wang R, Chen H, Xu F, Zang T, Pei Z, Wang Y, Shi B, Shen L, Ge J
Advanced Science 2023
Deciphering the causal relationship between blood pressure and regional white matter integrity: A two-sample Mendelian randomization study.
Ye Z, Mo C, Liu S, Gao S, Feng L, Zhao B, Canida T, Wu YC, Hatch KS, Ma Y, Mitchell BD, Hong LE, Kochunov P, Chen C, Zhao B, Chen S, Ma T
Journal of Neuroscience Research 2023
Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci
Hodonsky CJ, Turner AW, Khan MD, Barrientos NB, Methorst R, Ma L, Lopez NG, Mosquera JV, Auguste G, Farber E, Ma WF, Wong D, Onengut-Gumuscu S, Kavousi M, Peyser PA, van der Laan SW, Leeper NJ, Kovacic JC, Björkegren JL, Miller CL
2023
The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases
A Alsheikh, S Wollenhaupt, E King, J Reeb, S Ghosh, L Stolzenburg, S Tamim, J Lazar, J Davis, H Jacob
BMC Medical Genomics 2022
Redefining tissue specificity of genetic regulation of gene expression in the presence of allelic heterogeneity
M Arvanitis, K Tayeb, B Strober, A Battle
The American Journal of Human Genetics 2022
Unfolding the genotype-to-phenotype black box of cardiovascular diseases through cross-scale modeling.
Xi X, Li H, Chen S, Lv T, Ma T, Jiang R, Zhang P, Wong WH, Zhang X
iScience 2022
A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage.
Alexander MR, Hank S, Dale BL, Himmel L, Zhong X, Smart CD, Fehrenbach DJ, Chen Y, Prabakaran N, Tirado B, Centrella M, Ao M, Du L, Shyr Y, Levy D, Madhur MS
Circulation research 2022
Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases
CC Tseng, MC Wong, WT Liao, CJ Chen, SC Lee, JH Yen, SJ Chang
International journal of molecular sciences 2021
A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings
Q Li, M Dibus, A Casey, CS Yee, SO Vargas, S Luo, SM Rosen, JA Madden, CA Genetti, J Brabek, CA Brownstein, S Kazerounian, BA Raby, K Schmitz-Abe, JC Kennedy, MP Fishman, MP Mullen, JM Taylor, D Rosel, PB Agrawal, RQ Cron
PLoS genetics 2021
The actin depolymerizing factor destrin serves as a negative feedback inhibitor of smooth muscle cell differentiation
KA Liao, KV Rangarajan, X Bai, JM Taylor, CP Mack
American journal of physiology. Heart and circulatory physiology 2021
Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension
C Li, L Ma, Q Wang, X Shao, L Guo, J Chen, W Wang, J Yu
Journal of Hypertension 2021
Crispr-Cas9 deletion of hepatic Angiotensinogen gene results in sustained control of Hypertension: A Potential for Cure?
Sun H, Hodgkinson CP, Pratt RE, Dzau VJ
2021
Transcriptional and posttranscriptional regulation of the SMC-selective blood pressure-associated gene, ARHGAP42
KD Mangum, EJ Freeman, JC Magin, JM Taylor, CP Mack
American journal of physiology. Heart and circulatory physiology 2020
Transforming growth factor β‐mediated micromechanics modulates disease progression in primary myelofibrosis
P Teodorescu, S Pasca, A Jurj, G Gafencu, JP Joelsson, S Selicean, C Moldovan, R Munteanu, A Onaciu, AB Tigu, M Buse, AA Zimta, R Stiufiuc, B Petrushev, M Desmirean, D Dima, C Vlad, JT Bergthorsson, C Berce, S Ciurea, G Ghiaur, C Tomuleasa
Journal of Cellular and Molecular Medicine 2020
Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo
R Dee, X Bai, C Mack, J Taylor
Cells 2020
Comparative and Functional Genomic Resource for Mechanistic Studies of Human Blood Pressure–Associated Single Nucleotide Polymorphisms
M Mishra, E Liang, A Geurts, P Auer, P Liu, S Rao, A Greene, M Liang, Y Liu
Hypertension 2020
Over 1000 genetic loci influencing blood pressure with multiple systems and tissues implicated
CP Cabrera, FL Ng, HL Nicholls, A Gupta, MR Barnes, PB Munroe, MJ Caulfield
Human Molecular Genetics 2019
Haploinsufficiency of ARHGAP42 is associated with hypertension
AS Fjorder, MB Rasmussen, MM Mehrjouy, L Nazaryan-Petersen, C Hansen, M Bak, N Grarup, A Nørremølle, LA Larsen, H Vestergaard, T Hansen, N Tommerup, I Bache
European Journal of Human Genetics 2019
A polymorphism in intron I of the human angiotensinogen gene ( hAGT ) affects binding by HNF3 and hAGT expression and increases blood pressure in mice
B Mopidevi, MK Kaw, I Sivankutty, S Jain, SK Perla, A Kumar
The Journal of biological chemistry 2019
Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure
RA Dee, KD Mangum, X Bai, CP Mack, JM Taylor
Pharmacology & Therapeutics 2019
Brief Overview of a Decade of Genome-Wide Association Studies on Primary Hypertension
AB Azam, EA Azizan
International Journal of Endocrinology 2018
GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure
X Bai, K Mangum, M Kakoki, O Smithies, CP Mack, JM Taylor
Small GTPases 2017
Role of ARHGAP42 in hypertension
EF Carney
Nature Reviews Nephrology 2017

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