BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension-Reference-Cited by-同舟云学术

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

Published:2024-07-09 Issue:2 Volume:150 Page:132-150
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Shen Hui¹,Gao Ya¹^ORCID,Ge Dedong¹,Tan Meng¹,Yin Qing¹,Wei Tong-You Wade²^ORCID,He Fangzhou³^ORCID,Lee Tzong-Yi⁴,Li Zhongyan⁴,Chen Yuqin⁵,Yang Qifeng⁵,Liu Zhangyu¹,Li Xinxin¹,Chen Zixuan¹^ORCID,Yang Yi¹,Zhang Zhengang¹,Thistlethwaite Patricia A.⁶^ORCID,Wang Jian⁵⁷^ORCID,Malhotra Atul⁸,Yuan Jason X.-J.⁹^ORCID,Shyy John Y.-J.²,Gong Kaizheng¹^ORCID

Affiliation:

1. 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.).

2. Division of Cardiology (T.-Y.W.W., J.Y.-J.S.), University of California, San Diego, La Jolla.

3. Institute of Cardiovascular Science, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, China (F.H.).

4. Warshel Institute for Computational Biology, School of Medicine, Chinese University of Hong Kong, Shenzhen, China (T.-Y.L., Z.L.).

5. 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.).

6. Department of Medicine, Division of Cardiothoracic Surgery (P.A.T.), University of California, San Diego, La Jolla.

7. Guangzhou National Laboratory, Guangzhou International Bio Island, China (J.W.).

8. Division of Pulmonary and Critical Care Medicine (A.M.), University of California, San Diego, La Jolla.

9. Division of Pulmonary, Critical Care and Sleep Medicine (J.X.-J.Y.), University of California, San Diego, La Jolla.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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