平滑肌细胞的表观遗传改变调控内皮素依赖性血压和高血压动脉重塑

Kevin D Mangum, Qinmengge Li, Tyler Bauer, Sonya Wolf, James Shadiow, Jadie Yoonjoo Moon, Emily Barrett, Amrita Joshi, Zara Ahmed, Rachael Wasikowski, Kylie Boyer, Andrea Tara Obi, Frank M Davis, Lin Chang, Lam C Tsoi, Johann E. Gudjonsson, Katherine Ann Gallagher
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引用次数: 0

摘要

长期高血压(HTN)会影响多个器官系统,并导致病理性动脉重塑,而动脉重塑主要是由平滑肌细胞(SMC)的可塑性驱动的。尽管全基因组关联研究(GWAS)发现了许多与人类血压变化相关的变异基因,但这些变异基因中只有一小部分会真正导致高血压。为了确定在高血压和高血脂中对 SMC 功能有重要影响的相关基因,我们筛选了三项独立的人类 GWAS 和孟德尔随机化研究,以确定位于非编码基因区域内的 SNPs,重点是编码表观遗传酶的基因,因为最近已确定这些基因能控制心血管疾病中 SMC 的命运。我们发现了人类 JMJD3 基因启动子中的 SNP rs62059712 和 rs74480102,并证明小等位基因 C 通过增加 SP1 与 JMJD3 启动子的结合,增加了 SMC 中 JMJD3 的转录。利用我们的新型 SMC 特异性 Jmjd3 基因缺陷小鼠模型(Jmjd3flox/floxMyh11CreERT),我们发现 SMC 中 Jmjd3 基因的缺失会导致高血压,其机理是 EDNRB 表达的减少和 EDNRA 表达的代偿性增加。通过对人体动脉进行单细胞 RNA 测序(scRNA-seq),我们发现 JMJD3 和 EDNRB 在 SMCs 中的表达存在很强的相关性。此外,我们还发现 JMJD3 是 SMC 特异性基因表达所必需的,而在 HTN 的情况下,SMC 中 JMJD3 的缺失会促进 SMC 合成表型,从而导致动脉重塑加剧。我们的发现将高血压相关人类 DNA 变异与 SMC 可塑性调控联系起来,揭示了可用于高血压筛查和/或个性化治疗的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling
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 human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression 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.
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