Evidence map›Paper›PMID 32755395›Full record

ArticleCirculation2020

MDM2-Mediated Ubiquitination of Angiotensin-Converting Enzyme 2 Contributes to the Development of Pulmonary Arterial Hypertension.

Hui Shen, Jiao Zhang, Chen Wang, Pritesh P Jain, Mingmei Xiong, Xinxing Shi, Yuyang Lei, Shanshan Chen, Qian Yin, Patricia A Thistlethwaite and 5 more

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

Article in Circulation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.

0numbers the graph read from it
0cells of the map it votes in
78citing papers in PubMed
9.6field-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

78 citing papers in PubMed, 126 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Review
  10. ACE2: Friend or Foe in Post-COVID-19 Neurodegeneration?International journal of molecular sciences · 2025
    Review
  11. Review
  12. Review
  13. Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Evaluation of Angiotensin-Converting Enzyme 2 ExpressionACS pharmacology & translational science · 2024
    Article
  19. Review
  20. Article

18 more citing papers are in PubMed but not listed here.

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

15 authors at 5 institutions in 2 countries.

Hui Shen *Department of Cardiology, the Affiliated Hospital of Yangzhou University, Yangzhou University, China (H.S., K.G.).
Jiao Zhang *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (J.Z., C.W., Y.L., Z.-Y.Y.).
Chen Wang *Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (J.Z., C.W., Y.L., Z.-Y.Y.).
Pritesh P JainDivision of Pulmonary, Critical Care and Sleep Medicine (P.P.J., M.X., J.W., J.X.-J.Y.), University of California, San Diego, La Jolla.
Mingmei XiongDivision of Pulmonary, Critical Care and Sleep Medicine (P.P.J., M.X., J.W., J.X.-J.Y.), University of California, San Diego, La Jolla.
Xinxing Shi
Yuyang LeiDepartment of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (J.Z., C.W., Y.L., Z.-Y.Y.).
Shanshan ChenCardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (J.Z., C.W., Y.L., S.C., Q.Y.).
Qian YinCardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (J.Z., C.W., Y.L., S.C., Q.Y.).
Patricia A ThistlethwaiteDivision of Cardiothoracic Surgery, Department of Surgery (P.A.T.), University of California, San Diego, La Jolla.
Jian WangDivision of Pulmonary, Critical Care and Sleep Medicine (P.P.J., M.X., J.W., J.X.-J.Y.), University of California, San Diego, La Jolla.
Kaizheng GongDepartment of Cardiology, the Affiliated Hospital of Yangzhou University, Yangzhou University, China (H.S., K.G.).
Zu-Yi YuanDepartment of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (J.Z., C.W., Y.L., Z.-Y.Y.).
Jason X-J YuanDivision of Pulmonary, Critical Care and Sleep Medicine (P.P.J., M.X., J.W., J.X.-J.Y.), University of California, San Diego, La Jolla.
John Y-J ShyyDivision of Cardiology, Department of Medicine (J.Z., J.Y.-J.S.), University of California, San Diego, La Jolla.
University of California San Diego · USFirst Affiliated Hospital of Xi'an Jiaotong University · CNNorthern Jiangsu People's Hospital · CNXi'an Jiaotong University · CNUniversity of California System · US

Funding

Systems Biology Analyses for Hemodynamic Regulation of Vascular HomeostasisR01HL108735 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHIEN, SHU, SHYY, JOHN YJ · 2012 to 2024
$13.4M
Shear Regulation of MicroRNA Transportomes and Targetomes in Vascular HomeostasisR01HL106579 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHIEN, SHU, SHYY, JOHN YJ · 2011 to 2022
$8.3M
Molecular Mechanisms of Pulmonary HypertensionR01HL070852 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI THISTLETHWAITE, PATRICIA A · 2002 to 2011
$3.1M
NHLBI NIH HHS R01 HL070852NHLBI NIH HHS R01 HL106579NHLBI NIH HHS R01 HL108735
6 · The paper itself

Abstract

backgroundAngiotensin-converting enzyme 2 (ACE2) converts angiotensin II, a potent vasoconstrictor, to angiotensin-(1-7) and is also a membrane protein that enables coronavirus disease 2019 (COVID-19) infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of posttranslational modification of ACE2 in vascular endothelial cells is causative of a pulmonary hypertension (PH)-protective phenotype. The oncoprotein MDM2 (murine double minute 2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the posttranslational modification of ACE2 through its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH.

methodsBioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH.

resultsLevels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell-specific AMPKα2 knockout mitigated PH.

conclusionsMaladapted posttranslational modification (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.

Indexed as

UbiquitinationAMP-Activated Protein KinasesAngiotensin-Converting Enzyme 2AnimalsDisease SusceptibilityEndothelial CellsLungMiceMice, Inbred C57BLMice, KnockoutPeptidyl-Dipeptidase APolymorphism, Single NucleotideProto-Oncogene Proteins c-mdm2Pulmonary Arterial HypertensionRatsRNA InterferenceACE2 protein, humanAce2 protein, mouseAce2 protein, ratAMP-Activated Protein KinasesAngiotensin-Converting Enzyme 2Peptidyl-Dipeptidase APrkaa2 protein, mouseProto-Oncogene Proteins c-mdm2RNA, Small Interferingangiotensin-converting enzyme 2endotheliumMDM2 protein, humanpulmonary arterial hypertensionvascular remodeling

Identifiers

PMID32755395
PMCPMC7497891
OpenAlexW3045720050

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.