Haiyang Tang, Akash Gupta, Seth A. Morrisroe, Changlei Bao, Tae-Hwi Schwantes-An, Geetanjali Gupta, Shuxin Liang, Yanan Sun, Aiai Chu, Ang Luo, Venkateswaran Ramamoorthi Elangovan, Shreya Sangam, Yinan Shi, Samisubbu R. Naidu, Jia-Rong Jheng, Sultan Ciftci-Yilmaz, Noel A. Warfel, Louise Hecker, Sumegha Mitra, Anna W. Coleman, Katie A. Lutz, Michael W. Pauciulo, Yen-Chun Lai, Ali Javaheri, Rohan Dharmakumar, Wen-Hui Wu, Daniel P. Flaherty, Jason H. Karnes, Sandra Breuils-Bonnet, Olivier Boucherat, Sebastien Bonnet, Jason X.-J. Yuan, Jeffrey R. Jacobson, Julio D. Duarte, William C. Nichols, Joe G.N. Garcia, Ankit A. Desai
First Affiliated Hospital of Guangzhou Medical University. University of Arizona. Indiana University. Northwest A & F University. Gansu Provincial Hospital. Guangdong Academy of Sciences. University of Michigan. Emory University and Atlanta VA Healthcare System. Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine. Washington University in St. Louis and John Cochran VA Hospital. Université Laval. Purdue University. University of California, San Diego. University of Illinois at Chicago. University of Florida.
China, United States and Canada
Circulation
Circulation 2024;
DOI: 10.1161/CIRCULATIONAHA.123.065304
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.
Conclusions: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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