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

Area of Science:

• Genetics
• Cardiovascular Biology
• Molecular Biology

Background:

• Selective expression of Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) regulates blood pressure.
• ARHGAP42 inhibits RhoA-dependent contractility, providing a mechanism for blood pressure regulation.
• Hypertension is a complex condition with genetic and cellular components.

Purpose of the Study:

• Identify polymorphisms affecting ARHGAP42 expression.
• Assess ARHGAP42's role in hypertension development.
• Investigate the functional impact of ARHGAP42 genetic variations.

Main Methods:

• DNase I hypersensitivity assays and ENCODE data analysis to identify regulatory elements.
• CRISPR/Cas9 gene editing to delete identified regulatory elements in human SMCs.
• DNA binding and transcription assays to determine the effect of ARHGAP42 single nucleotide polymorphisms (SNPs).

Main Results:

• A regulatory element containing ARHGAP42 SNP rs604723 with SMC-selective, allele-specific activity was identified.
• Deletion of this element reduced ARHGAP42 expression in cultured human SMCs.
• The minor T allele at rs604723 increased regulatory element activity by enhancing transcription factor binding, leading to higher ARHGAP42 expression.
• ARHGAP42 deletion exacerbated hypertension in a mouse model.
• ARHGAP42 genotype was associated with hypertension risk in human patients.

Conclusions:

• A specific genetic variation (rs604723) in ARHGAP42 influences its expression in SMCs.
• This variation impacts blood pressure regulation and hypertension risk.
• ARHGAP42 represents a potential therapeutic target for individualized antihypertensive strategies.