Mangum Kevin D, Li Qinmengge, Hartmann Katherine, Bauer Tyler M, Wolf Sonya J, Shadiow James, Moon Jadie Y, Barrett Emily C, Joshi Amrita D, Saldana de Jimenez Gabriela, Ahmed Zara, Wasikowski Rachael, Boyer Kylie, Obi Andrea T, Davis Frank M, Chang Lin, Tsoi Lam C, Gudjonsson Johann, Damrauer Scott M, Gallagher Katherine A
Section of Vascular Surgery, Department of Surgery.
Department of Microbiology and Immunology, and.
J Clin Invest. 2025 Mar 27;135(11). doi: 10.1172/JCI186146. eCollection 2025 Jun 2.
Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating SMC function in HTN, we considered Genome Wide Association Studies (GWAS) of blood pressure, focusing on genes encoding epigenetic enzymes, which control SMC fate in cardiovascular disease. Using statistical fine mapping of the KDM6 Jumonji domain-containing protein D3 (JMJD3) locus, we found that rs62059712 is the most likely casual variant, with each major T allele copy associated with a 0.47 mmHg increase in systolic blood pressure. We show that the T allele decreased JMJD3 transcription in SMCs via decreased SP1 binding to the JMJD3 promoter. Using our unique SMC-specific Jmjd3-deficient murine model (Jmjd3fl/flMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased endothelin receptor B (EDNRB) expression and increased endothelin receptor A (EDNRA) expression. Importantly, the EDNRA antagonist BQ-123 reversed HTN after Jmjd3 deletion in vivo. Additionally, single-cell RNA-Seq (scRNA-Seq) of human arteries revealed a strong correlation between JMJD3 and EDNRB in SMCs. Further, JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs increased HTN-induced arterial remodeling. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing targets that may be used in personalized management of HTN.
长期高血压（HTN）会影响多个器官，并导致病理性动脉重塑，这是由平滑肌细胞（SMC）可塑性驱动的。为了确定在高血压中调节SMC功能的相关基因，我们考虑了血压的全基因组关联研究（GWAS），重点关注编码表观遗传酶的基因，这些酶在心血管疾病中控制SMC的命运。通过对含KDM6 Jumonji结构域蛋白D3（JMJD3）基因座的统计精细定位，我们发现rs62059712是最可能的偶然变体，每个主要的T等位基因拷贝与收缩压升高0.47 mmHg相关。我们表明，T等位基因通过减少SP1与JMJD3启动子的结合而降低了SMC中JMJD3的转录。使用我们独特的SMC特异性Jmjd3缺陷小鼠模型（Jmjd3fl/flMyh11CreERT），我们表明SMC中Jmjd3的缺失会导致高血压，原因是内皮素受体B（EDNRB）表达降低和内皮素受体A（EDNRA）表达增加。重要的是，EDNRA拮抗剂BQ-123在体内Jmjd3缺失后逆转了高血压。此外，人类动脉的单细胞RNA测序（scRNA-Seq）显示SMC中JMJD3与EDNRB之间存在强相关性。此外，JMJD3是SMC特异性基因表达所必需的，SMC中JMJD3的缺失增加了高血压诱导的动脉重塑。我们的研究结果将一种与高血压相关的人类DNA变体与SMC可塑性的调节联系起来，揭示了可用于高血压个性化管理的靶点。
