Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension

• DOI: 10.1161/circulationaha.123.065304
• Publication Date: 2024-05-02T09:00:39Z
• Authors: Haiyang Tang; Akash Gupta; Seth A. Morrisroe; Changlei Bao; Tae-Hwi Schwantes-An; Geetanjali Gupta; Shuxin Liang; Yanan Sun; Aiai Chu; Ang Luo; Venkateswaran Ram...; 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-Bo...; Olivier Boucherat; Sebastien Bonnet; Jason X.-J. Yuan; Jeffrey R. Jacobson; Julio D. Duarte; William C. Nichols; Joe G.N. Garcia; Ankit A. Desai
• Keywords: 0303 health sciences; 03 medical and health sciences

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.