Pulmonary vascular disease & thromboembolism
Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension
Authors' conclusion
Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.
Study context
- Population
- Preclinical pulmonary arterial hypertension (PAH) models (rats, mice), human pulmonary artery endothelial and smooth muscle cells, and patients with PAH
- Comparison
- UCHL1 deficiency or inhibition vs UCHL1 intact
Main finding
As reported in the abstract
- Increased vascular UCHL1 staining and protein expression in animal PH models and in pulmonary artery endothelial cells from patients with PAH
- UCHL1 inhibitor LDN57444 reduced human pulmonary artery endothelial and smooth muscle cell proliferation
- Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1-/- rats and Tie2Cre-Uchl1fl/fl mice showed reduced RV hypertrophy, RV systolic pressures and obliterative vascular remodeling
- Uchl1-/- lungs and pulmonary artery endothelial cells: reduced total and activated Akt, increased ubiquitinated Akt
- UCHL1-silenced human pulmonary artery endothelial cells: reduced K63-linked and increased K48-linked AKT1
Further findings
UCHL1 variant rs9321 in humans
- Associated with reduced methylation (n=5133)
- Associated with increased UCHL1 gene expression in lungs (n=815)
- Associated with reduced cardiac index in patients (n=796)
Gadd45α-/- mice
- Reduced lung vascular UCHL1 and AKT1 expression with attenuated hypoxic PH
Original publication
Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension. Circulation. Published 2 May 2024. doi:10.
Summarised from the published abstract; every number is checked against it