Chromobox 3 assembles an epigenetic complex contributing to cystathionine γ-lyase-mediated protection against aortic aneurysm/dissection.
Summary
This mechanistic study identifies a CSE/H2S–CBX3 epigenetic axis that restrains ADAMTS4-driven ECM remodeling in aortic aneurysm/dissection. CSE deficiency reduces CBX3, while H2S-induced CBX3 sulfhydration stabilizes CBX3; AAV-mediated Cse or Cbx3 delivery mitigates AAD in mice.
Key Findings
- CSE expression is reduced in VSMCs from human AAD and AngII-induced male mouse models; VSMC-specific Cse deletion exacerbates AAD.
- Cse deficiency downregulates CBX3, releasing repression of Adamts4; a CBX3-centered complex (SUV39H1, KDM2A, HDAC1, RING1) coordinates histone modifications to regulate ECM/apoptosis/inflammation genes.
- H2S induces CBX3 sulfhydration (C69, C160, C177), stabilizing CBX3 by reducing ubiquitin-mediated degradation; AAV-mediated Cse or Cbx3 delivery attenuates AAD progression in mice.
Clinical Implications
Suggests therapeutic strategies that enhance CSE/H2S signaling or stabilize CBX3, and supports ADAMTS4-versican pathway modulation as a target in AAD. Provides a rationale for biomarker development (CSE/CBX3) and preclinical gene therapy approaches.
Why It Matters
It reveals a novel, targetable epigenetic mechanism linking H2S signaling to ECM homeostasis in AAD and demonstrates therapeutic rescue via gene delivery.
Limitations
- Predominant use of male murine models may limit sex-specific generalizability.
- Preclinical gene therapy findings require validation in large animals and human tissues with longitudinal outcomes.
Future Directions
Evaluate CSE/CBX3 modulation in large-animal AAD models; develop small-molecule CBX3 stabilizers or ADAMTS4 inhibitors; assess CSE/CBX3 as biomarkers for patient stratification.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic animal and cellular studies with human tissue correlates.
- Study Design
- OTHER