Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in MiceNovelty and Significance
Jump to

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Angiotensin II (Ang II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II–induced AF in immunosubunit PSMB10 (also known as β2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/min per kg). PSMB10 expression and trypsin-like activity were increased in atrial tissues and serum from Ang II–treated mice or serum from patients with AF. Moreover, Ang II–infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10–treated mice. Administration of IKKβ-specific inhibitor IMD 0354 reduced Ang II–induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-β–Smad2/3 signaling leading to cardiac fibrosis but also induced IKKβ activation and ubiquitin-mediated degradation of IkBα ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1β, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II–induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF.
- Received September 26, 2017.
- Revision received October 14, 2017.
- Accepted February 11, 2018.
- © 2018 American Heart Association, Inc.
Novelty and Significance
American Heart Association Professional?
Log in using your username and password
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
This Issue
Jump to
Article Tools
- Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in MiceNovelty and SignificanceJing Li, Shuai Wang, Jie Bai, Xiao-Lei Yang, Yun-Long Zhang, Yi-Lin Che, Hui-Hua Li and Yan-Zong YangHypertension. 2018;71:866-876, originally published March 5, 2018https://doi.org/10.1161/HYPERTENSIONAHA.117.10390
Citation Manager Formats
Share this Article
- Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in MiceNovelty and SignificanceJing Li, Shuai Wang, Jie Bai, Xiao-Lei Yang, Yun-Long Zhang, Yi-Lin Che, Hui-Hua Li and Yan-Zong YangHypertension. 2018;71:866-876, originally published March 5, 2018https://doi.org/10.1161/HYPERTENSIONAHA.117.10390