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.

LanguageEnglish (US)
Pages670-680
Number of pages11
JournalJournal of Clinical Investigation
Volume127
Issue number2
DOIs
StatePublished - Feb 1 2017

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Serum Response Factor
Smooth Muscle Myocytes
Blood Pressure
Hypertension
DNA
Alleles
Clustered Regularly Interspaced Short Palindromic Repeats
Desoxycorticosterone Acetate
Deoxyribonuclease I
Antihypertensive Agents
Single Nucleotide Polymorphism
Hypersensitivity
Transcription Factors
Salts
Genotype
Genes
Therapeutics
rho GTPase-activating protein
sphingosine 1-phosphate

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding",
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.",
author = "Xue Bai and Mangum, {Kevin D.} and Dee, {Rachel A.} and Stouffer, {George A.} and Lee, {Craig R.} and Akinyemi Oni-Orisan and Cam Patterson and Schisler, {Jonathan C.} and Viera, {Anthony J.} and Taylor, {Joan M.} and Mack, {Christopher P.}",
year = "2017",
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T1 - Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

AU - Bai,Xue

AU - Mangum,Kevin D.

AU - Dee,Rachel A.

AU - Stouffer,George A.

AU - Lee,Craig R.

AU - Oni-Orisan,Akinyemi

AU - Patterson,Cam

AU - Schisler,Jonathan C.

AU - Viera,Anthony J.

AU - Taylor,Joan M.

AU - Mack,Christopher P.

PY - 2017/2/1

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AB - 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.

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