Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

Autor:	Tang H; 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.)., Gupta A; 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.)., Morrisroe SA; 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., Bao C; 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.).; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi)., Schwantes-An TH; Department of Medicine, and Departments of Medical & Molecular Genetics (T.-H.S.-A.), Indiana University, Indianapolis., Gupta G; 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.)., Liang S; 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.)., Sun Y; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi)., Chu A; Department of Echocardiography, Gansu Provincial Hospital, Lanzhou, China (A.C.)., Luo A; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).; Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China (A.L.)., Ramamoorthi Elangovan V; Department of Pediatrics, University of Michigan, Ann Arbor (V.R.E.)., Sangam S; 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., Shi Y; 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.; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi)., Naidu SR; 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., Jheng JR; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.-C.L.), Indiana University, Indianapolis., Ciftci-Yilmaz S; 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., Warfel NA; 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.)., Hecker L; Department of Medicine, Emory University, and Atlanta VA Healthcare System, GA (L.H.)., Mitra S; 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.)., Coleman AW; 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.)., Lutz KA; 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.)., Pauciulo MW; 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.)., Lai YC; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (J.-R.J., Y.-C.L.), Indiana University, Indianapolis., Javaheri A; 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.)., Dharmakumar R; 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., Wu WH; 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.)., Flaherty DP; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Lafayette, IN (D.P.F.)., Karnes JH; Department of Pharmacy Practice and Science, R Ken Coit College of Pharmacy, University of Arizona, Tucson (J.H.K.)., Breuils-Bonnet S; 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.)., Boucherat O; 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.)., Bonnet S; 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.)., Yuan JX; Department of Medicine, University of California, San Diego, La Jolla (J.X.-J.Y.)., Jacobson JR; Department of Medicine, University of Illinois at Chicago (J.R.J.)., Duarte JD; Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville (J.D.D.)., Nichols WC; 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.)., Garcia JGN; The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter (J.G.N.G.)., Desai AA; 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.
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2024 Jul 23; Vol. 150 (4), pp. 302-316. Date of Electronic Publication: 2024 May 02.
DOI:	10.1161/CIRCULATIONAHA.123.065304
Abstrakt:	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. Competing Interests: None.
Databáze:	MEDLINE
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