Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension-Reference-Cited by-同舟云学术

Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension

Published:2024-07-23 Issue:4 Volume:150 Page:302-316
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Tang Haiyang¹^ORCID,Gupta Akash²^ORCID,Morrisroe Seth A.³^ORCID,Bao Changlei¹⁴^ORCID,Schwantes-An Tae-Hwi⁵^ORCID,Gupta Geetanjali²^ORCID,Liang Shuxin¹^ORCID,Sun Yanan⁴,Chu Aiai⁶,Luo Ang⁴⁷^ORCID,Ramamoorthi Elangovan Venkateswaran⁸^ORCID,Sangam Shreya³^ORCID,Shi Yinan³⁴,Naidu Samisubbu R.³^ORCID,Jheng Jia-Rong⁹^ORCID,Ciftci-Yilmaz Sultan³,Warfel Noel A.²^ORCID,Hecker Louise¹⁰,Mitra Sumegha¹¹,Coleman Anna W.¹²,Lutz Katie A.¹²^ORCID,Pauciulo Michael W.¹²^ORCID,Lai Yen-Chun⁹^ORCID,Javaheri Ali¹¹^ORCID,Dharmakumar Rohan³,Wu Wen-Hui¹³,Flaherty Daniel P.¹⁴^ORCID,Karnes Jason H.¹⁵^ORCID,Breuils-Bonnet Sandra¹³,Boucherat Olivier¹³^ORCID,Bonnet Sebastien¹³^ORCID,Yuan Jason X.-J.¹⁶^ORCID,Jacobson Jeffrey R.¹⁷^ORCID,Duarte Julio D.¹⁸^ORCID,Nichols William C.¹²^ORCID,Garcia Joe G.N.¹⁹^ORCID,Desai Ankit A.³^ORCID

Affiliation:

1. 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.).

2. 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.).

3. Krannert Cardiovascular Research Center (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.), Indiana University, Indianapolis.

4. College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).

5. Department of Medicine, and Departments of Medical & Molecular Genetics (T.-H.S.-A.), Indiana University, Indianapolis.

6. Department of Echocardiography, Gansu Provincial Hospital, Lanzhou, China (A.C.).

7. Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China (A.L.).

8. Department of Pediatrics, University of Michigan, Ann Arbor (V.R.E.).

9. Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.-C.L.), Indiana University, Indianapolis.

10. Department of Medicine, Emory University, and Atlanta VA Healthcare System, GA (L.H.).

11. Department of Obstetrics and Gynecology (S.M.), Department of Medicine, Washington University in St. Louis and John Cochran VA Hospital, St Louis, MO (A.J.).

12. Division 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.).

13. Department 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.).

14. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Lafayette, IN (D.P.F.).

15. Department of Pharmacy Practice and Science, R Ken Coit College of Pharmacy, University of Arizona, Tucson (J.H.K.).

16. Department of Medicine, University of California, San Diego, La Jolla (J.X.-J.Y.).

17. Department of Medicine, University of Illinois at Chicago (J.R.J.).

18. Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville (J.D.D.).

19. The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter (J.G.N.G.).

Abstract

BACKGROUND: The 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. METHODS: Tissues 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, Uchl1 knockout rats ( Uchl1 −/− ), and conditional Uchl1 knockout mice ( Tie2Cre-Uchl1 fl/fl ) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1 −/− animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice ( Gadd45α −/− ) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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