ArticleCirculation2024
Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.
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Article in Circulation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 19 citations in OpenAlex.
- The Deubiquitinase UCHL1 Drives Susceptibility to Atrial Fibrillation by Stabilizing CaMKII-δ.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Deubiquitinases as Regulators and Therapeutic Targets in Vascular Diseases.International journal of molecular sciences · 2026Review
- Exploring the Toxicological Impacts of DOTP Exposure on Pulmonary Arterial Hypertension via Network Toxicology, Virtual Knockout, Molecular Docking and Experimental Validation.International journal of molecular sciences · 2026Article
- The Emerging Role of UCHL1 in Neurological and Musculoskeletal Diseases.Immunology and cell biology · 2026Review
- Post-translational modification crosstalk in pulmonary arterial hypertension: mechanisms and therapeutic implications.Molecular biology reports · 2026Review
- Variation inCirculation research · 2026Article
- Article
- Emerging significance of E3 ubiquitin ligases and Deubiquitinases in pulmonary hypertension.Molecular medicine (Cambridge, Mass.) · 2026Review
- Article
- The role of ubiquitination in the pathogenesis of atrial fibrillation: mechanisms and therapeutic implications.Frontiers in pharmacology · 2026Review
- UCHL1 stabilizes Twist1 via K11/K63-linked deubiquitination to drive tumor metastasis in non-small cell lung cancer.Cell death discovery · 2025Article
- Animal models of hypertension and concurrent organs injury.Animal models and experimental medicine · 2025Review
- Article
- The role of lactate metabolism and lactylation in pulmonary arterial hypertension.Respiratory research · 2025Review
- USP11 Promotes Endothelial Apoptosis-Resistance in Pulmonary Arterial Hypertension by Deubiquitinating HINT3.Journal of respiratory biology and translational medicine · 2025Article
- Bioactive compound combinations fromFrontiers in pharmacology · 2025Article
- Mortality and trends of pulmonary arterial hypertension, 1990-2021: a population-based study.Frontiers in cardiovascular medicine · 2025Article
- Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.Respiratory research · 2024Article
- Ubiquitin C-terminal hydrolase L1 is a regulator of tumor growth and metastasis in double-negative prostate cancer.American journal of clinical and experimental urology · 2024Article
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Authors and funding
37 authors at 16 institutions in 5 countries.
Haiyang Tang *State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (H.T., C.B., S.L.).ORCID 0000-0001-9537-2891
Akash Gupta *Department of Medicine and Arizona Health Sciences Center, Department of Cellular and Molecular Medicine, College of Medicine-Tucson, University of Arizona (A.G., G.G., N.A.W.).ORCID 0000-0001-7305-055X
Seth A MorrisroeKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.ORCID 0009-0003-1418-2730
Changlei BaoState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (H.T., C.B., S.L.).ORCID 0000-0002-1773-3986
Tae-Hwi Schwantes-AnDepartment of Medicine, and Departments of Medical & Molecular Genetics (T.-H.S.-A.), Indiana University, Indianapolis.ORCID 0000-0001-6387-0095
Geetanjali GuptaDepartment of Medicine and Arizona Health Sciences Center, Department of Cellular and Molecular Medicine, College of Medicine-Tucson, University of Arizona (A.G., G.G., N.A.W.).ORCID 0009-0002-6493-3689
Shuxin LiangState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China (H.T., C.B., S.L.).ORCID 0000-0002-5663-5326
Yanan SunCollege of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).
Aiai ChuDepartment of Echocardiography, Gansu Provincial Hospital, Lanzhou, China (A.C.).
Ang LuoCollege of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).ORCID 0000-0002-7831-6430
Venkateswaran Ramamoorthi ElangovanDepartment of Pediatrics, University of Michigan, Ann Arbor (V.R.E.).ORCID 0000-0002-3597-2307
Shreya SangamKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.ORCID 0000-0002-4913-6713
Yinan ShiKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.
Samisubbu R NaiduKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.ORCID 0000-0001-9411-660X
Jia-Rong JhengDivision of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.-C.L.), Indiana University, Indianapolis.ORCID 0000-0002-9210-8611
Sultan Ciftci-YilmazKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.
Noel A WarfelDepartment of Medicine and Arizona Health Sciences Center, Department of Cellular and Molecular Medicine, College of Medicine-Tucson, University of Arizona (A.G., G.G., N.A.W.).ORCID 0000-0001-6410-9011
Louise HeckerDepartment of Medicine, Emory University, and Atlanta VA Healthcare System, GA (L.H.).
Sumegha MitraDepartment of Obstetrics and Gynecology (S.M.), Department of Medicine, Washington University in St. Louis and John Cochran VA Hospital, St Louis, MO (A.J.).
Anna W ColemanDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH (A.W.C., K.A.L., M.W.P., W.C.N.).
Katie A LutzDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH (A.W.C., K.A.L., M.W.P., W.C.N.).ORCID 0000-0002-9554-7679
Michael W PauciuloDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH (A.W.C., K.A.L., M.W.P., W.C.N.).ORCID 0000-0002-2141-2966
Yen-Chun LaiDivision of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.-C.L.), Indiana University, Indianapolis.ORCID 0000-0002-4703-5708
Ali JavaheriDepartment of Obstetrics and Gynecology (S.M.), Department of Medicine, Washington University in St. Louis and John Cochran VA Hospital, St Louis, MO (A.J.).ORCID 0000-0001-6657-331X
Rohan DharmakumarKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.
Wen-Hui WuDepartment of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada (W.-H.W., S.B.-B., O.B., S.B.).
Daniel P FlahertyDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Lafayette, IN (D.P.F.).ORCID 0000-0002-8305-0606
Jason H KarnesDepartment of Pharmacy Practice and Science, R Ken Coit College of Pharmacy, University of Arizona, Tucson (J.H.K.).ORCID 0000-0001-5001-3334
Sandra Breuils-BonnetDepartment of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada (W.-H.W., S.B.-B., O.B., S.B.).
Olivier BoucheratDepartment of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada (W.-H.W., S.B.-B., O.B., S.B.).ORCID 0000-0002-5251-7488
Sebastien BonnetDepartment of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada (W.-H.W., S.B.-B., O.B., S.B.).ORCID 0000-0001-5753-1900
Jason X-J YuanDepartment of Medicine, University of California, San Diego, La Jolla (J.X.-J.Y.).ORCID 0000-0002-0685-4862
Jeffrey R JacobsonDepartment of Medicine, University of Illinois at Chicago (J.R.J.).ORCID 0000-0001-8929-994X
Julio D DuarteCenter for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville (J.D.D.).ORCID 0000-0001-9766-4038
William C NicholsDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH (A.W.C., K.A.L., M.W.P., W.C.N.).ORCID 0000-0003-1242-9237
Joe G N GarciaThe Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter (J.G.N.G.).ORCID 0000-0002-6934-0420
Ankit A DesaiKrannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.ORCID 0000-0001-6427-616X
Anna Needs Neuroblastoma Answers · USCincinnati Children's Hospital Medical Center · USInstitut universitaire de cardiologie et de pneumologie de Québec · CANorth West Agriculture and Forestry University · CNUniversity of Arizona · USIndiana University – Purdue University Indianapolis · USFirst Affiliated Hospital of Guangzhou Medical University · CNJohn Cochran VA Medical Center · USEmory Healthcare · USGansu Provincial Hospital · CNPharmacoGenetics (China) · CNPurdue University West Lafayette · USScripps Research Institute · USSri Venkateswara University · INUniversity of California San Diego · USUniversity of Illinois Chicago · US
Funding
National Biological Sample and Data Repository for PAHR24HL105333 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI NICHOLS, WILLIAM C · 2012 to 2016
$10.1MRole of Skeletal Muscle in Pulmonary Vascular RemodelingR01HL142638 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI Yen Chun Charly Lai · 2018 to 2026
$4.9MNovel Involvement of NAMPT and TLR4 in PAH Vascular RemodelingR01HL141387 · NHLBI · UNIVERSITY OF FLORIDA · PI Joe G. N. Garcia, Ayako Makino · 2019 to 2026
$3.8MRisk stratification in pulmonary arterial hypertension: Intersection of OMICs and longitudinal phenotypes through the PAH BiobankR01HL160941 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI DESAI, ANKIT A, NICHOLS, WILLIAM C · 2022 to 2025
$3.2MPathogenic Role of IL-18 in Sickle Cell Cardiomyopathy and Inducible Ventricular TachycardiaR01HL136603 · NHLBI · UNIVERSITY OF ARIZONA · PI DESAI, ANKIT A · 2017 to 2021
$2.4MLeveraging the Microbiome, Local Admixture, and Machine Learning to Optimize Anticoagulant Pharmacogenomics in Medically Underserved PatientsR01HL158686 · NHLBI · UNIVERSITY OF ARIZONA · PI KARNES, JASON HANSEN · 2021 to 2025
$2.2MABO and Immunogenetic Variation in the Pathogenesis of Heparin-Induced ThrombocytopeniaR01HL156993 · NHLBI · UNIVERSITY OF ARIZONA · PI KARNES, JASON HANSEN · 2022 to 2025
$2.0MPreclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary HypertensionR42HL164300 · NHLBI · AQUALUNG THERAPEUTICS CORP. · PI GARCIA, JOE G. N. · 2022 to 2024
$1.9MBLRD VA I01 BX006003NHLBI NIH HHS R01 HL136603NHLBI NIH HHS R01 HL141387NHLBI NIH HHS R01 HL142638NHLBI NIH HHS R01 HL156993NHLBI NIH HHS R01 HL158686NHLBI NIH HHS R01 HL160941NHLBI NIH HHS R24 HL105333NHLBI NIH HHS R42 HL164300
Abstract
backgroundThe ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1.
methodsTissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals,
resultsSupporting experimental data, we found that rs9321, a variant in a GC-enriched region of the
conclusionsOur findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.
Indexed as
Mice, KnockoutProto-Oncogene Proteins c-aktUbiquitin ThiolesteraseAnimalsCell ProliferationCells, CulturedDisease Models, AnimalEndothelial CellsHumansHypertension, PulmonaryIndolesMaleMiceMice, Inbred C57BLOximesPulmonary Arterial HypertensionIndolesLDN 57444OximesProto-Oncogene Proteins c-aktUbiquitin ThiolesteraseUCHL1 protein, humanUchl1 protein, mouseUCHL1 protein, ratmodels, animalpulmonary arterial hypertensionubiquitination
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