Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling

Abstract

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the humanJMJD3gene and show that the minor C allele increasesJMJD3transcription in SMCs via increased SP1 binding to theJMJD3promoter. Using our novel SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss ofJmjd3in SMCs results in HTN, mechanistically, due to decreasedEDNRBexpression and a compensatory increase inEDNRAexpression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation betweenJMJD3andEDNRBexpression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.Graphical Abstract