Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

Tang, Haiyang; Gupta, Akash; Morrisroe, Seth A; Bao, Changlei; Schwantes-An, Tae-Hwi; Gupta, Geetanjali; Liang, Shuxin; Sun, Yanan; Chu, Aiai; Luo, Ang; Ramamoorthi Elangovan, Venkateswaran; Sangam, Shreya; Shi, Yinan; Naidu, Samisubbu R; Jheng, Jia-Rong; Ciftci-Yilmaz, Sultan; Warfel, Noel A; Hecker, Louise; Mitra, Sumegha; Coleman, Anna W; Lutz, Katie A; Pauciulo, Michael W; Lai, Yen-Chun; Javaheri, Ali; Dharmakumar, Rohan; Wu, Wen-Hui; Flaherty, Daniel P; Karnes, Jason H; Breuils-Bonnet, Sandra; Boucherat, Olivier; Bonnet, Sebastien; Yuan, Jason X-J; Jacobson, Jeffrey R; Duarte, Julio D; Nichols, William C; Garcia, Joe G N; Desai, Ankit A

Tang, Haiyang; Gupta, Akash; Morrisroe, Seth A; Bao, Changlei; Schwantes-An, Tae-Hwi; Gupta, Geetanjali; Liang, Shuxin; Sun, Yanan; Chu, Aiai; Luo, Ang; Ramamoorthi Elangovan, Venkateswaran; Sangam, Shreya; Shi, Yinan; Naidu, Samisubbu R; Jheng, Jia-Rong; Ciftci-Yilmaz, Sultan; Warfel, Noel A; Hecker, Louise; Mitra, Sumegha; Coleman, Anna W; Lutz, Katie A; Pauciulo, Michael W; Lai, Yen-Chun; Javaheri, Ali; Dharmakumar, Rohan; Wu, Wen-Hui; Flaherty, Daniel P; Karnes, Jason H; Breuils-Bonnet, Sandra; Boucherat, Olivier; Bonnet, Sebastien; Yuan, Jason X-J; Jacobson, Jeffrey R; Duarte, Julio D; Nichols, William C; Garcia, Joe G N; Desai, Ankit A.

Afiliación

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, Indiana University, Indianapolis. (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.).
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.).
Schwantes-An TH; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).
Gupta G; Department of Medicine, and Departments of Medical & Molecular Genetics, Indiana University, Indianapolis. (T.-H.S.-A.).
Liang S; 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.).
Sun Y; 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.).
Chu A; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).
Luo A; Department of Echocardiography, Gansu Provincial Hospital, Lanzhou, China (A.C.).
Ramamoorthi Elangovan V; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).
Sangam S; Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China (A.L.).
Shi Y; Department of Pediatrics, University of Michigan, Ann Arbor (V.R.E.).
Naidu SR; Krannert Cardiovascular Research Center, Indiana University, Indianapolis. (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.).
Jheng JR; Krannert Cardiovascular Research Center, Indiana University, Indianapolis. (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.).
Ciftci-Yilmaz S; College of Veterinary Medicine, Northwest A & F University, Yangling, China (C.B., Y. Sun, A.L., Y. Shi).
Warfel NA; Krannert Cardiovascular Research Center, Indiana University, Indianapolis. (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.).
Hecker L; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University, Indianapolis. (J.-R.J., Y.-C.L.).
Mitra S; Krannert Cardiovascular Research Center, Indiana University, Indianapolis. (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.).
Coleman AW; 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.).
Lutz KA; Department of Medicine, Emory University, and Atlanta VA Healthcare System, GA (L.H.).
Pauciulo MW; Department of Obstetrics and Gynecology (S.M.).
Lai YC; 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.).
Javaheri A; 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.).
Dharmakumar R; 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.).
Wu WH; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University, Indianapolis. (J.-R.J., Y.-C.L.).
Flaherty DP; Department of Medicine, Washington University in St. Louis and John Cochran VA Hospital, St Louis, MO (A.J.).
Karnes JH; Krannert Cardiovascular Research Center, Indiana University, Indianapolis. (S.A.M., S.S., Y. Shi, S.R.N., S.C.-Y., R.D., A.A.D.).
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 Medicinal Chemistry and Molecular Pharmacology, Purdue University, Lafayette, IN (D.P.F.).
Bonnet S; Department of Pharmacy Practice and Science, R Ken Coit College of Pharmacy, University of Arizona, Tucson (J.H.K.).
Yuan JX; 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.).
Jacobson JR; 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.).
Duarte JD; 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.).
Nichols WC; Department of Medicine, University of California, San Diego, La Jolla (J.X.-J.Y.).
Garcia JGN; Department of Medicine, University of Illinois at Chicago (J.R.J.).
Desai AA; Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville (J.D.D.).

Circulation ; 2024 May 02.

Article en En | MEDLINE | ID: mdl-38695173

ABSTRACT

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-Uchl1fl/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.