Pulmonary vascular disease & thromboembolism
BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension
Authors' conclusion
These results suggest a pivotal role of BRCC3 in sustaining pulmonary vascular homeostasis by maintaining the integrity of the BMP signaling (ie, the ALK2-Smad1/5-PPARγ axis) while suppressing TGF-β signaling in PASMCs.
Study context
- Population
- Pulmonary artery smooth muscle cells (PASMCs), mouse models and specimens from patients with idiopathic pulmonary arterial hypertension (PAH)
Main finding
As reported in the abstract
- BRCC3 significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension
- BRCC3 de-ubiquitinates ALK2 at Lys-472 and Lys-475, activating Smad1/5/9 and transcription of BMP-regulated PPARγ, p53 and Id1
- BRCC3 overexpression attenuated TGF-β signaling (lower TGF-β expression, inhibited Smad3 phosphorylation)
- BRCC3 overexpression or ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced apoptosis in vitro
- SM22α-BRCC3-Tg mice: pulmonary hypertension ameliorated via ALK2-Smad1/5-PPARγ axis activation
- Brcc3-/- mice: increased susceptibility to experimental pulmonary hypertension via inhibited ALK2-Smad1/5 signaling
Original publication
BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension. Circulation. Published 1 April 2024. doi:10.
Summarised from the published abstract; every number is checked against it