Article Impact Level: HIGH Data Quality: STRONG Summary of Journal of Clinical Investigation, 135(11), e186146. https://doi.org/10.1172/JCI186146 Dr. Kevin D. Mangum et al.
Points
- A common genetic variant, rs62059712, is linked to higher blood pressure by reducing the expression of the epigenetic enzyme JMJD3 in blood vessel walls.
- This reduction of JMJD3 upsets a critical balance by increasing endothelin receptor-A levels while decreasing endothelin receptor-B, which causes blood vessels to constrict more readily.
- Over the long term, this imbalance not only elevates blood pressure but also promotes harmful arterial remodeling, which can increase the subsequent risk of heart attack and stroke.
- Researchers confirmed this mechanism in mouse models, where deleting JMJD3 from smooth muscle cells caused high blood pressure driven by the altered endothelin receptor signaling.
- The compound BQ-123, which targets the overactive endothelin receptor-A, successfully reversed hypertension in the mice, suggesting a potential personalized treatment for genetically susceptible individuals.
Summary
This study investigated the role of the epigenetic enzyme Jumonji domain-containing protein D3 (JMJD3) in the pathophysiology of hypertension (HTN) and associated arterial remodeling. Using statistical fine mapping of Genome-Wide Association Studies (GWAS) data, researchers identified rs62059712 as the most likely causal variant in the KDM6 locus. Each copy of the major T allele, present in approximately 90% of the population, was associated with a 0.47 mmHg increase in systolic blood pressure. The study demonstrated that this T allele decreases JMJD3 transcription in vascular smooth muscle cells (SMCs) by impairing the binding of the SP1 transcription factor to the JMJD3 promoter.
To elucidate the mechanism, researchers utilized an SMC-specific Jmjd3-deficient murine model (Jmjd3fl/flMyh11CreERT). Loss of Jmjd3 in SMCs induced HTN by altering endothelin receptor expression, specifically causing a decrease in endothelin receptor B (EDNRB) and a corresponding increase in endothelin receptor A (EDNRA) levels. This shift promotes vasoconstriction and exacerbates HTN-induced arterial remodeling through increased endothelin-ERK signaling. The correlation between JMJD3 and EDNRB expression in SMCs was further confirmed in human arterial tissue via single-cell RNA-Seq.
The findings highlight a potential personalized therapeutic strategy. In the murine model, the selective EDNRA antagonist BQ-123 administration successfully reversed hypertension following Jmjd3 deletion. This suggests that targeting the overactive EDNRA pathway could benefit the large patient population carrying the rs62059712 variant. The study provides a direct mechanistic link between a common genetic variant, SMC plasticity, and blood pressure regulation, offering a clear target for personalized management of hypertension.
Link to the article: https://www.jci.org/articles/view/186146
References Mangum, K. D., Li, Q., Hartmann, K., Bauer, T. M., Wolf, S. J., Shadiow, J., Moon, J. Y., Barrett, E. C., Joshi, A. D., Saldana De Jimenez, G., Ahmed, Z., Wasikowski, R., Boyer, K., Obi, A. T., Davis, F. M., Chang, L., Tsoi, L. C., Gudjonsson, J., Damrauer, S. M., & Gallagher, K. A. (2025). Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling. Journal of Clinical Investigation, 135(11), e186146. https://doi.org/10.1172/JCI186146
