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Administration of USP7 inhibitor p22077 alleviates Angiotensin II (Ang II)-induced atrial fibrillation in Mice

Hypertension Research volume 47, pages 1309–1322 (2024)Cite this article

Abstract

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-β/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.

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Data availability

Every single record generated in the current investigation remains accessible to the corresponding authors following reasonable request. All the data obtained in the current study were available from the corresponding authors on reasonable request. All data necessary for evaluating the conclusions of the paper are included in the paper. The authors of this paper will provide any additional data which are requested.

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Funding

Funding

This study’s completion was funded by grants from the National Natural Science Foundation of China (82170320 to H.-L.B.); the Natural Science Foundation of Liaoning Provincial (2021-MS-279 to H.-L.B.); the Dalian Science Fund for Distinguished Young Scholars (2023RJ020 to H.-L.B.; 2022RJ13 to X.-L.Y.); Dalian Medical University Interdisciplinary Research Cooperation Project Team Funding (JCHZ2023023 to H.-L.B.).

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  1. These authors contributed equally: Yu Wang, Yu-Hui Gu.

Authors and Affiliations

  1. Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China

    Yu Wang, Yu-Hui Gu, Kai-Wen Ren, Shi-Hao Wang, Xiao-Xue Zhu, Lei Wang, Xiao-Lei Yang & Hai-Lian Bi

  2. Department of pharmacology, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China

    Xin Xie

  3. Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China

    Xiao-Lei Yang

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  1. Yu Wang
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Contributions

H.-L. B. and X.-L. Y. conceived the project. Y. W., Y.-H. G., K.-W. R., and X. X. performed the experiments and analyzed the data, S.-H. W., X.-X. Z. and L. W. were responsible for human clinical studies and analyses. H.-L. B., X.-L. Y. and Y. W. wrote the paper with input from all authors.

Corresponding authors

Correspondence to Xiao-Lei Yang or Hai-Lian Bi.

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Ethics

The Animal Care and Use Committee of Dalian Medical University assessed and authorized the laboratory study, which was conducted out in accordance with the US National Institutes of Health Studies involving human participants have been authorized by the First Affiliated Hospital of Dalian Medical University (PJ-KS-KY-2021-229).The animal study was assessed and authorised by the Animal Care and Use Committee of Dalian Medical University and carried out in accordance with the U.S. National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (publication no. 85-23, 1996). Studies involving human participants were approved by the First Affiliated Hospital of Dalian Medical University (PJ-KS-KY-2021-229).

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Wang, Y., Gu, YH., Ren, KW. et al. Administration of USP7 inhibitor p22077 alleviates Angiotensin II (Ang II)-induced atrial fibrillation in Mice. Hypertens Res 47, 1309–1322 (2024). https://doi.org/10.1038/s41440-024-01581-2

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