USP11 Promotes Endothelial Apoptosis-Resistance in Pulmonary Arterial Hypertension by Deubiquitinating HINT3
Year: 2025
Type: article
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.
Institutions: Emory University, Atlanta VA Health Care System, Atlanta VA Medical Center, University of Kansas, University of Kansas Medical Center, The Ohio State University, Georgia Institute of Technology, The Wallace H. Coulter Department of Biomedical Engineering, Allegheny Health Network, Louisiana State University, Louisiana State University Health Sciences Center Shreveport, Drexel University, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1319912306, G1586559204, G1944247121, G196810821, G2413216740, G3268080060, G3308670482, G3941227159, Alcohol-mediated Clock genes interfere with lung injury and repair, G6541757112, Pulmonary Hypertension Breakthrough Initiative, G7415795898, The Role of PPARy in the Pathogenesis and Therapy of Sickle Cell Disease-Pulmonary Hypertension, G8822248744, G9000046174, G9000248012, Mitochondrial deubiquitinase USP30 regulates cell metabolism-mediated miRNA biogenesis and microvascular inflammation
OpenAlex ID: W4408803419