Evidence map›Paper›PMID 38557054›Full record

ArticleCirculation2024

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

Hui Shen, Ya Gao, Dedong Ge, Meng Tan, Qing Yin, Tong-You Wade Wei, Fangzhou He, Tzong-Yi Lee, Zhongyan Li, Yuqin Chen and 12 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
10.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 26 citations in OpenAlex.

  1. Article
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  3. Hypertensive mt. tRNARedox biology · 2026
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors at 7 institutions in 2 countries.

Hui Shen *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.).
Ya Gao *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.).ORCID 0000-0002-1640-6246
Dedong GeDepartment 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.).
Meng TanDepartment 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.).
Qing YinDepartment 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.).
Tong-You Wade WeiDivision of Cardiology (T.-Y.W.W., J.Y.-J.S.), University of California, San Diego, La Jolla.ORCID 0000-0003-4578-5668
Fangzhou HeInstitute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, China (F.H.).ORCID 0000-0002-6853-6544
Tzong-Yi LeeWarshel Institute for Computational Biology, School of Medicine, Chinese University of Hong Kong, Shenzhen, China (T.-Y.L., Z.L.).
Zhongyan LiWarshel Institute for Computational Biology, School of Medicine, Chinese University of Hong Kong, Shenzhen, China (T.-Y.L., Z.L.).
Yuqin ChenState 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.).
Qifeng YangState 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.).
Zhangyu LiuDepartment 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.).
Xinxin LiDepartment 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.).
Zixuan ChenDepartment 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.).ORCID 0000-0002-9075-8776
Yi YangDepartment 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.).
Zhengang ZhangDepartment 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.).
Patricia A ThistlethwaiteDepartment of Medicine, Division of Cardiothoracic Surgery (P.A.T.), University of California, San Diego, La Jolla.ORCID 0000-0002-1986-7304
Jian WangState 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.).ORCID 0000-0002-1278-256X
Atul MalhotraDivision of Pulmonary and Critical Care Medicine (A.M.), University of California, San Diego, La Jolla.
Jason X-J YuanDivision of Pulmonary, Critical Care and Sleep Medicine (J.X.-J.Y.), University of California, San Diego, La Jolla.ORCID 0000-0002-0685-4862
John Y-J ShyyDivision of Cardiology (T.-Y.W.W., J.Y.-J.S.), University of California, San Diego, La Jolla.
Kaizheng GongDepartment 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.).ORCID 0000-0003-3239-2443
Yangzhou University · CNUniversity of California San Diego · USChinese University of Hong Kong, Shenzhen · CNFirst Affiliated Hospital of Guangzhou Medical University · CNGuangzhou Experimental Station · CNUniversity of California System · USXi'an Jiaotong University · CN

Funding

Is Obstructive Sleep Apnea Important in the Development of Alzheimer's DiseaseR01AG063925 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MALHOTRA, ATUL · 2020 to 2024
$3.7M
Underlying mechanisms of obesity-induced obstructive sleep apneaR01HL148436 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Atul Malhotra · 2020 to 2026
$3.4M
Sleep Apnea Endophenotypes: One Size Does Not Fit AllR01HL154926 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MALHOTRA, ATUL · 2021 to 2025
$3.3M
Molecular Mechanisms of Pulmonary HypertensionR01HL070852 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI THISTLETHWAITE, PATRICIA A · 2002 to 2011
$3.1M
The cardiovascular consequences of sleep apnea plus COPD (Overlap syndrome)R01HL166485 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Atul Malhotra · 2023 to 2026
$3.1M
VentNet: A Real-Time Multimodal Data Integration Model for Prediction of Respiratory Failure in Patients with COVID-19R01HL157985 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MALHOTRA, ATUL, NEMATI, SHAMIM · 2022 to 2025
$2.9M
Developing a Diverse Next Generation of Leaders in Respiratory ScienceT32HL166127 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Laura Elise Crotty Alexander, Atul Malhotra · 2023 to 2026
$1.6M
NHLBI NIH HHS R01 HL070852NHLBI NIH HHS R01 HL148436NHLBI NIH HHS R01 HL154926NHLBI NIH HHS R01 HL157985NHLBI NIH HHS R01 HL166485NHLBI NIH HHS T32 HL166127NIA NIH HHS R01 AG063925
6 · The paper itself

Abstract

backgroundAn 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.

methodsBioinformatic 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.

resultsBRCC3 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,

conclusionsThese 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.

Indexed as

Hypertension, PulmonaryMuscle, Smooth, VascularMyocytes, Smooth MuscleActivin Receptors, Type IActivin Receptors, Type IIAnimalsBone Morphogenetic Protein Receptors, Type IICell ProliferationCells, CulturedDeubiquitinating EnzymesDisease Models, AnimalHumansMaleMiceMice, Inbred C57BLMice, KnockoutActivin Receptors, Type IActivin Receptors, Type IIACVR1 protein, humanAcvr1 protein, mouseACVRL1 protein, humanAcvrl1 protein, mouseBone Morphogenetic Protein Receptors, Type IIBRCC3 protein, humanBRCC3 protein, mouseDeubiquitinating EnzymesPPAR gammaactivin receptor-like kinase-2bone morphogenetic proteinBRCC3 proteinpulmonary arterial hypertension

Identifiers

PMID38557054
PMCPMC11230848
OpenAlexW4393388869

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