Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling.

Summary

Fine-mapping identified a JMJD3 variant (rs62059712) that lowers SMC JMJD3 expression, shifting endothelin receptor balance (↓EDNRB, ↑EDNRA) and elevating blood pressure. SMC-specific Jmjd3 deletion caused hypertension and aggravated arterial remodeling, both reversed by ETA (EDNRA) antagonism (BQ-123). Single-cell human data supported a JMJD3–EDNRB link, defining a mechanistic, targetable axis for personalized hypertension therapy.

Key Findings

• Fine-mapping identified rs62059712 at JMJD3; each T allele increased SBP by ~0.47 mmHg and reduced SMC JMJD3 via decreased SP1 promoter binding.
• SMC-specific Jmjd3 deletion caused hypertension with ↓EDNRB and ↑EDNRA expression; ETA antagonism (BQ-123) reversed hypertension in vivo.
• Human arterial scRNA-Seq showed strong JMJD3–EDNRB correlation; loss of JMJD3 increased hypertension-induced arterial remodeling.

Clinical Implications

Genotype- and mechanism-informed use of endothelin receptor antagonists (e.g., ETA blockade) could benefit subsets of hypertensive patients with JMJD3/EDNRA–EDNRB dysregulation. The JMJD3 axis may also provide biomarkers for remodeling risk and response to endothelin-targeted therapy.

Limitations

• Translational gap: clinical efficacy of endothelin antagonism in genetically selected hypertensive patients remains to be tested.
• Effect sizes from the common variant are modest; additional loci and environmental factors likely contribute.

Future Directions

Prospective, genotype-enriched clinical trials of ETA/ETB antagonists; development of JMJD3/EDNRA–EDNRB biomarkers; exploration of epigenetic modulators restoring JMJD3 in SMCs.