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. Author manuscript; available in PMC: 2025 Jan 9.
Published in final edited form as: Circulation. 2024 Apr 1;150(2):132–150. doi: 10.1161/CIRCULATIONAHA.123.066430

Figure 8. Schematic illustration of the protective role of BRCC3 in PH alleviation.

Figure 8.

Under normal conditions, BRCC3 preserves the deubiquitination of ALK2, thus sustaining the phosphorylation of Smad1/5 and its nuclear entry to maintain the integrity of BMP pathway, which contributes to the contractile phenotype of PASMCs. Upon the onset of PAH, reduction of BRCC3 and increase in SMURF1 mediates the K63-linked ubiqutination of ALK2, leading to decreased ALK2 activity and phosphorylation and nuclear entry of Smad1/5, which promotes the proliferative phenotype of PASMCs. Pharmacological or genetic rectification of the BRCC3-ALK2 axis to rebalance BMP/TGF-β pathways may ameliorate PH in rodents and humans. ALK2 indicates activin receptor-like kinase-2; BMP, bone morphogenetic protein; BRCC3, BRCA1/BRCA2-containing complex subunit 3; PAH, pulmonary arterial hypertension; PASMC, pulmonary arterial smooth muscle cell; PH, pulmonary hypertension; SMURF1, Smad ubiquitination regulatory factor 1; and TGF-β, transforming growth factor-β.