ASH2L Deficiency in Smooth Muscle Drives Pulmonary Vascular Remodeling.
Summary
ASH2L is downregulated in human pulmonary arteries in PH and correlates with disease severity. Loss of ASH2L promotes smooth muscle proliferation and vascular remodeling through a KLF5–FBXW7 complex that regulates KLF5 protein stability and NOTCH3 transcription; pharmacologic KLF5 inhibition attenuated PH in hypoxic SMC-specific models.
Key Findings
- ASH2L was the only SET1/MLL member differentially expressed in PH lung vessels, decreased in pulmonary arteries and correlated with PH severity.
- ASH2L loss promoted SMC proliferation and vascular remodeling; restoration ameliorated these phenotypes.
- Mechanistically, ASH2L formed a complex with KLF5 and FBXW7 to drive KLF5 degradation; ASH2L loss enhanced KLF5 recruitment to the NOTCH3 promoter, increasing NOTCH3 expression.
- Pharmacologic KLF5 blockade attenuated PH in chronic hypoxia SMC-specific models.
Clinical Implications
KLF5 inhibition or restoration of ASH2L function may serve as therapeutic strategies in pulmonary hypertension; biomarkers based on ASH2L/KLF5/NOTCH3 could support stratification.
Why It Matters
Reveals a druggable epigenetic/transcriptional axis (ASH2L–KLF5–NOTCH3) driving pulmonary vascular remodeling, directly linking human specimens to mechanistic models and therapeutic intervention.
Limitations
- Clinical translation remains to be established; safety/efficacy of targeting KLF5 or ASH2L in humans is unknown.
- Quantitative sample sizes and full in vivo efficacy details are not provided in the abstract.
Future Directions
Evaluate KLF5/NOTCH3 axis inhibitors and ASH2L activators in preclinical PH models and explore biomarker development for patient stratification.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic study combining human tissue analysis with cellular and animal models to define a causal pathway.
- Study Design
- OTHER