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.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mangum
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Dee
authors.forename: George A
authors.initials: GA
authors.lastname: Stouffer
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.forename: Akinyemi
authors.initials: A
authors.lastname: Oni-Orisan
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Viera
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mack
mesh_terms: D000818:Animals; D001794:Blood Pressure; D064113:CRISPR-Cas Systems; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C476858:SRF protein, human; D026362:Serum Response Factor; D017673:Sodium Chloride, Dietary; C000589232:ARHGAP42 protein, human; C066737:RHOA protein, human; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein