Bum-Yong Kang, Jiwoong Choi, Victor Tseng, Yutong Zhao, Jing Zhao, Robert S. Stearman, Wilbur A. Lam, Viranuj Sueblinvong, Benjamin T. Kopp, Michael J. Passineau, Changwon Park, John Lister, Raymond J. Benza, Andrew J. Jang
Emory University School of Medicine. Atlanta Veterans Healthcare System. University of Kansas School of Medicine and University of Kansas. Ansible Health. Ohio State University. University of Indiana. Georgia Institute of Technology. Allegheny Health Network. Louisiana State University Health Science Center. Drexel University College of Medicine. Ichan School of Medicine and Mount Sinai Fuster Heart Hospital.
United States
Journal of Respiratory Biology Translational Medicine
J Respir Biol Transl Med 2025;
DOI: 10.70322/jrbtm.2025.10002
Abstract
Pulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. A previous genome-wide association study (GWAS) with Affymetrix microarray analysis data exhibited elevated histidine triad nucleotide-binding protein 3 (HINT3) in the lung samples of PAH compared to control subjects (failed donors, FD) and the positive correlations of HINT3 with deubiquitinase USP11 and B-cell lymphoma 2 (BCL2). In this study, we aim to investigate the roles and interplay of USP11 and HINT3 in the apoptosis resistance of PAH. The levels of USP11 and HINT3 were increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice. USP11 and HINT3 interacted physically, as shown by co-immunoprecipitation (co-IP) assay in human pulmonary arterial endothelial cells (HPAECs). HINT3 was degraded by polyubiquitination, which was reversed by USP11. Furthermore, HINT3 interacted with the anti-apoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, the knockdown of HINT3 function led to a depletion of BCL2. Thus, we conclude that USP11 stabilizes HINT3 activation, which contributes to endothelial apoptosis-resistance of pulmonary arterial endothelial cells in PAH. This can potentially be a novel therapeutic target for ubiquitination modulators for PAH.
Category
Class I. Idiopathic Pulmonary Hypertension
Genetic Factors Associated with Pulmonary Vascular Disease
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Animal Models of Pulmonary Vascular Disease and Therapy
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes