First Author | Li J | Year | 2018 |
Journal | Hypertension | Volume | 71 |
Issue | 5 | Pages | 866-876 |
PubMed ID | 29507100 | Mgi Jnum | J:311583 |
Mgi Id | MGI:6771772 | Doi | 10.1161/HYPERTENSIONAHA.117.10390 |
Citation | Li J, et al. (2018) Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II-Induced Atrial Fibrillation in Mice. Hypertension 71(5):866-876 |
abstractText | 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 beta2i 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 IKKbeta-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-beta-Smad2/3 signaling leading to cardiac fibrosis but also induced IKKbeta activation and ubiquitin-mediated degradation of IkBalpha ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1beta, 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. |