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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Bai, X; Mangum, KD; Dee, RA; Stouffer, GA; Lee, CR; Oni-Orisan, A; Patterson, C; Schisler, JC; Viera, AJ; Taylor, JM; Mack, CP

Published Date

  • February 2017

Published In

Volume / Issue

  • 127 / 2

Start / End Page

  • 670 - 680

PubMed ID

  • 28112683

Pubmed Central ID

  • 28112683

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI88899

Language

  • eng