BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

Autor:	Shen H; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Gao Y; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Ge D; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Tan M; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Yin Q; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Wei TW; Division of Cardiology (T.-Y.W.W., J.Y.-J.S.), University of California, San Diego, La Jolla., He F; Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, China (F.H.)., Lee TY; Warshel Institute for Computational Biology, School of Medicine, Chinese University of Hong Kong, Shenzhen, China (T.-Y.L., Z.L.)., Li Z; Warshel Institute for Computational Biology, School of Medicine, Chinese University of Hong Kong, Shenzhen, China (T.-Y.L., Z.L.)., Chen Y; State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, China (Y.C., Q. Yang, J.W.)., Yang Q; State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, China (Y.C., Q. Yang, J.W.)., Liu Z; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Li X; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Chen Z; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Yang Y; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Zhang Z; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.)., Thistlethwaite PA; Department of Medicine, Division of Cardiothoracic Surgery (P.A.T.), University of California, San Diego, La Jolla., Wang J; State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, China (Y.C., Q. Yang, J.W.).; Guangzhou National Laboratory, Guangzhou International Bio Island, China (J.W.)., Malhotra A; Division of Pulmonary and Critical Care Medicine (A.M.), University of California, San Diego, La Jolla., Yuan JX; Division of Pulmonary, Critical Care and Sleep Medicine (J.X.-J.Y.), University of California, San Diego, La Jolla., Shyy JY; Division of Cardiology (T.-Y.W.W., J.Y.-J.S.), University of California, San Diego, La Jolla., Gong K; Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, China (H.S., Y.G., D.G., M.T., Q. Yin, Z.L., X.L., Z.C., Y.Y., Z.Z., K.G.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2024 Jul 09; Vol. 150 (2), pp. 132-150. Date of Electronic Publication: 2024 Apr 01.
DOI:	10.1161/CIRCULATIONAHA.123.066430
Abstrakt:	Background: An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-β (transforming growth factor-β) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-β family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-βR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination. By modulating the posttranslational modifications of the BMP/TGF-β-PPARγ pathway, BRCC3 may play a role in pulmonary vascular remodeling, hence the pathogenesis of PAH. Methods: Bioinformatic analyses were used to explore the mechanism by which BRCC3 deubiquitinates ALK2. Cultured pulmonary artery smooth muscle cells (PASMCs), mouse models, and specimens from patients with idiopathic PAH were used to investigate the rebalance between BMP and TGF-β signaling in regulating ALK2 phosphorylation and ubiquitination in the context of pulmonary hypertension. Results: BRCC3 was significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension. BRCC3, by de-ubiquitinating ALK2 at Lys-472 and Lys-475, activated receptor-regulated Smad1/5/9, which resulted in transcriptional activation of BMP-regulated PPARγ, p53, and Id1. Overexpression of BRCC3 also attenuated TGF-β signaling by downregulating TGF-β expression and inhibiting phosphorylation of Smad3. Experiments in vitro indicated that overexpression of BRCC3 or the de-ubiquitin-mimetic ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced PASMC apoptosis. In SM22α-BRCC3-Tg mice, pulmonary hypertension was ameliorated because of activation of the ALK2-Smad1/5-PPARγ axis in PASMCs. In contrast, Brcc3 -/- mice showed increased susceptibility of experimental pulmonary hypertension because of inhibition of the ALK2-Smad1/5 signaling. Conclusions: 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. Such rebalance of BMP/TGF-β pathways is translationally important for PAH alleviation. Competing Interests: None.
Databáze:	MEDLINE
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