Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.

IF 5.8 2区医学 Q1 Medicine Respiratory Research Pub Date : 2024-08-29 DOI:10.1186/s12931-024-02953-5

Rui Wang, Rui Wang, Siqi Zhou, Tianya Liu, Jingjing Dang, Qianmin Chen, Jingyu Chen, Zhiping Wang

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Abstract

Objectives: In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH).

Methods: Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH.

Results: The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression.

Conclusions: NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.

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血管紧张素转换酶2的泛素化有助于神经前体细胞表达的发育下调基因4-Like介导的肺动脉高压的发病。

研究目的本研究探讨了神经前体细胞表达的发育下调基因4样（NEDD4L）是否是血管紧张素转换酶2（ACE2）的E3酶，以及NEDD4L是否通过泛素化降解ACE2，从而导致肺动脉高压（PAH）的进展：方法：利用生物信息学分析探索泛素化 ACE2 的 E3 连接酶。培养的肺动脉平滑肌细胞（PASMCs）和 PAH 患者的标本被用来研究 PAH 背景下 NEDD4L 和 ACE2 之间的串联及其泛素化：结果：泛素化的抑制减轻了缺氧诱导的PASMCs增殖。在 PAH 患者的肺组织和 PASMCs 中，NEDD4L 的水平升高，ACE2 的水平降低。NEDD4L是ACE2的E3连接酶，可能通过泛素化介导的降解抑制了ACE2在PASMCs中的表达。PAH 与 NEDD4L 表达上调和 ACE2 表达下调有关：结论：ACE2 的 E3 泛素化酶 NEDD4L 可促进 PASMC 的增殖，最终导致 PAH。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.