Kang Bum-Yong, Choi Jiwoong, Tseng Victor, Zhao Yutong, Zhao Jing, Stearman Robert S, Lam Wilbur A, Sueblinvong Viranuj, Kopp Benjamin T, Passineau Michael J, Park Changwon, Lister John, Benza Raymond J, Jang Andrew J
Department of Pediatrics, Division of Pulmonology, Asthma, Cystic Fibrosis, and Sleep, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
J Respir Biol Transl Med. 2025 Mar;2(1). doi: 10.70322/jrbtm.2025.10002. Epub 2025 Mar 24.
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.
肺动脉高压（PAH）是一种进行性、致命且无法治愈的肺血管疾病。先前一项利用Affymetrix微阵列分析数据进行的全基因组关联研究（GWAS）显示，与对照受试者（失败供体，FD）相比，PAH患者肺样本中的组氨酸三联体核苷酸结合蛋白3（HINT3）升高，且HINT3与去泛素化酶USP11和B细胞淋巴瘤2（BCL2）呈正相关。在本研究中，我们旨在探究USP11和HINT3在PAH细胞凋亡抵抗中的作用及相互作用。特发性PAH（IPAH）患者和低氧/苏金单抗处理小鼠的肺组织中USP11和HINT3水平升高。在人肺动脉内皮细胞（HPAECs）中进行的免疫共沉淀（co-IP）分析表明，USP11和HINT3存在物理相互作用。HINT3通过多聚泛素化被降解，而USP11可逆转这种降解。此外，HINT3与抗凋亡介质BCL2相互作用。USP11的过表达增加了BCL2的含量，这与IPAH患者和低氧/苏金单抗处理小鼠肺组织中BCL2水平升高一致。相反，HINT3功能的敲低导致BCL2减少。因此，我们得出结论，USP11稳定HINT3的激活，这有助于PAH中肺动脉内皮细胞的内皮细胞凋亡抵抗。这可能是PAH泛素化调节剂的一个新的治疗靶点。
