USP11 Promotes Endothelial Apoptosis-Resistance in Pulmonary Arterial Hypertension by Deubiquitinating HINT3

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.

Authors

Institutions

Publication Details

Journal
Journal of Respiratory Biology and Translational Medicine
Published
2025-01-01
DOI
https://doi.org/10.70322/jrbtm.2025.10002
Citations
1
Primary Topic
Pulmonary Hypertension Research and Treatments
Type
article
Field-Weighted Citation Impact
1.52

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

USP11 Promotes Endothelial Apoptosis-Resistance in Pulmonary Arterial Hypertension by Deubiquitinating HINT3

Jiwoong Choi, Victor Tseng, Yutong Zhao, Bum‐Yong Kang et al.
1 citations
Journal of Respiratory Biology and Translational Medicine
Pulmonary Hypertension Research and Treatments
1.52
article

USP11 Promotes Endothelial Apoptosis-Resistance in Pulmonary Arterial Hypertension by Deubiquitinating HINT3

Jiwoong Choi, Victor Tseng, Yutong Zhao, Bum‐Yong Kang, Michael J. Passineau, Andrew J. Jang, Benjamin T. Kopp, Zhao Jing, Wilbur Aaron Lam, Viranuj Sueblinvong, Robert S. Stearman, John Lister, Changwon Park, Raymond J. Benza
article en
1 citations

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.

Journal of Respiratory Biology and Translational MedicineVol. 2(1)
Georgia Institute of Technology (US), Allegheny Health Network (US), University of Kansas (US), Emory University (US), Cystic Fibrosis Foundation (US), The Wallace H. Coulter Department of Biomedical Engineering (US), Mount Sinai Hospital (US), Mount Sinai Hospital (US), Deep Space Industries (United States) (US), University of Kansas Medical Center (US), Atlanta VA Health Care System (US), The Ohio State University (US), Indiana University – Purdue University Indianapolis (US), Drexel University (US), Louisiana State University Health Sciences Center Shreveport (US)
Cardiovascular Medical Research and Education Fund, National Institutes of Health, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Zero hunger
Openalex Percentile: Top 21%
Pulmonary Hypertension Research and Treatments
1.52
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.