Evidence map›Paper›PMID 39601126›Full record

ArticleHypertension (Dallas, Tex. : 1979)2025

UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension.

Mona Elgazzaz, Navya Lakkappa, Clara Berdasco, Uma Priya Mohan, Anna Nuzzo, Luke Restivo, Alexa Martinez, Amy Scarborough, Jessie J Guidry, Srinivas Sriramula and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Hypertension (Dallas, Tex. : 1979), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
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

6 citing papers in PubMed.

  1. Brain and hypertension: from sympathetic outflow to brain-focused blood pressure management.Hypertension research : official journal of the Japanese Society of Hypertension · 2026
    Review
  2. Review
  3. Article
  4. Analysis of modifying factors for ACE2 to work effectively.Hypertension research : official journal of the Japanese Society of Hypertension · 2025
    Article
  5. Article
  6. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors.

Mona Elgazzaz *Cardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0002-8437-2789
Navya Lakkappa *Cardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0003-2079-5675
Clara BerdascoCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0001-6704-9763
Uma Priya MohanCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0003-2757-0735
Anna NuzzoCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.
Luke RestivoCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0009-0008-2438-1529
Alexa MartinezCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0001-9376-5368
Amy ScarboroughCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0002-8275-891X
Jessie J GuidryCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0002-5601-0430
Srinivas SriramulaCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0001-9937-1589
Jiaxi XuCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0002-0694-813X
Hisham DaoudSchool of Computer and Cyber Sciences, Augusta University, GA (H.D.).ORCID 0000-0002-2067-7575
Michelle A Mendiola PláDivision of Surgical Sciences, Department of Surgery, Duke University, Durham, NC (M.A.M.P., D.E.B.).ORCID 0000-0001-9348-7708
Dawn E BowlesDivision of Surgical Sciences, Department of Surgery, Duke University, Durham, NC (M.A.M.P., D.E.B.).
Andreas M BeyerDepartment of Medicine, Medical College of Wisconsin, Milwaukee, WI (A.M.B.).ORCID 0000-0001-9129-7492
Franck Mauvais-JarvisSoutheast Louisiana Veterans Health Care System, New Orleans, LA (M.E., N.L., C.B., U.P.M., F.M.-J., E.L.).ORCID 0000-0002-0874-0754
Xinping YueCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0002-4834-6612
Catalin M FilipeanuCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.
Eric LazartiguesCardiovascular Center of Excellence (M.E., N.L., C.B., U.P.M., A.N., L.R., A.M., A.S., J.J.G., S.S., J.X., X.Y., C.M.F., E.L.), New Orleans, LA.ORCID 0000-0001-7290-0786

Funding

Targeting the estrogen receptor-α to protect functional β-cell mass in womenR01DK074970 · NIDDK · TULANE UNIVERSITY OF LOUISIANA · PI Franck Mauvais-Jarvis · 2007 to 2026
$6.0M
Vascular and Cardiac Function Core - "Mentoring in Cardiovascular BiologyP30GM106392 · NIGMS · LSU HEALTH SCIENCES CENTER · PI KAPUSTA, DANIEL R · 2014 to 2018
$5.5M
Targeting ACE2 ubiquitination for hypertensionR01HL150592 · NHLBI · LSU HEALTH SCIENCES CENTER · PI LAZARTIGUES, ERIC D · 2020 to 2023
$2.4M
Targeting ADAM17 maturation in resistant hypertension.R01HL163588 · NHLBI · LSU HEALTH SCIENCES CENTER · PI LAZARTIGUES, ERIC D · 2022 to 2025
$2.2M
Critical role of Mitochondrial Fission/Fusion in Regulation of Microvascular Endothelial FunctionR01HL157025 · NHLBI · MEDICAL COLLEGE OF WISCONSIN · PI BEYER, ANDREAS M · 2021 to 2024
$2.1M
Mechanism of Chemotherapy Induced Microvascular Dysfunction in Cancer SurvivorsR01HL173549 · NHLBI · MEDICAL COLLEGE OF WISCONSIN · PI Andreas M Beyer · 2024 to 2026
$2.1M
BLRD VA I01 BX004294BLRD VA IK2 BX005218NHLBI NIH HHS R01 HL150592NHLBI NIH HHS R01 HL157025NHLBI NIH HHS R01 HL163588NHLBI NIH HHS R01 HL173549NIDDK NIH HHS R01 DK074970NIGMS NIH HHS P30 GM106392
6 · The paper itself

Abstract

backgroundAng-II (angiotensin II) impairs the function of the antihypertensive enzyme ACE2 (angiotensin-converting enzyme 2) by promoting its internalization, ubiquitination, and degradation, thus contributing to hypertension. However, few ACE2 ubiquitination partners have been identified, and their role in hypertension remains unknown.

methodsProteomics and bioinformatic analyses were used to identify ACE2 ubiquitination partners in the brain, heart, and kidney of hypertensive C57BL6/J mice of both sexes. The interaction between UBR1 (ubiquitin protein ligase E3 component N-recognin) and ACE2 was validated in cells. Central and peripheral UBR1 knockdown was then performed in male mice to investigate its role in the maintenance of hypertension.

resultsProteomics analysis of the hypothalamus identified UBR1 as a potential E3 (ubiquitin protein ligase) ligase promoting ACE2 ubiquitination. Enhanced UBR1 expression, associated with ACE2 reduction, was confirmed in various tissues from hypertensive male mice and human samples. Treatment of endothelial and smooth muscle cells with testosterone, but not 17β-estradiol, confirmed a sex-specific regulation of UBR1. In vivo silencing of UBR1 using chronic administration of small interference RNA resulted in the restoration of ACE2 levels in hypertensive male mice. A transient decrease in blood pressure after intracerebroventricular, but not systemic, infusion was also observed. Interestingly, UBR1 knockdown increased brain activation of Nedd4-2 (neural precursor cell expressed developmentally downregulated protein 4), an E3 ligase promoting ACE2 ubiquitination, and reduced expression of serum and glucocorticoid-regulated kinase 1, the kinase that inactivates Nedd4-2.

conclusionsThese data demonstrate that UBR1 is a novel E3 ubiquitin ligase targeting ACE2 in hypertension. UBR1 and Nedd4-2 appear to work synergistically to ubiquitinate ACE2. Targeting these ubiquitin ligases may represent a novel strategy to restore ACE2 compensatory activity in hypertension.

Indexed as

Angiotensin-Converting Enzyme 2HypertensionUbiquitinationUbiquitin-Protein LigasesAnimalsBlood PressureDisease Models, AnimalFemaleHumansMaleMiceMice, Inbred C57BLNedd4 Ubiquitin Protein LigasesPeptidyl-Dipeptidase ASex FactorsACE2 protein, humanAce2 protein, mouseAngiotensin-Converting Enzyme 2Nedd4 Ubiquitin Protein LigasesPeptidyl-Dipeptidase AUbiquitin-Protein Ligasesangiotensin-converting enzyme 2blood pressureestrogenshypertensionhypothalamus

Identifiers

PMID39601126
PMCPMC11655255

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Registered trials

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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.