Immunoproteasome Subunit β5i Promotes Ang II (Angiotensin II)–Induced Atrial Fibrillation by Targeting ATRAP (Ang II Type I Receptor–Associated Protein) Degradation in Mice

Abstract

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and increases the risk of stroke, heart failure, and death. Ang II (angiotensin II) triggers AF, mainly through stimulation of the AT1R (Ang II type I receptor). The immunoproteasome is a highly efficient proteolytic machine derived from the constitutive proteasome, but the role it plays in regulating AT1R activation and triggering AF remains unknown. Here, we show that among the catalytic subunits, β5i (PSMB8) expression, and chymotrypsin-like activity were the most significantly upregulated in atrial tissue of Ang II–infused mice or serum from patients with AF. β5i KO (β5i knockout) in mice markedly attenuated Ang II-induced AF incidence, atrial fibrosis, inflammatory response, and oxidative stress compared with WT (wild type) animals, but injection with recombinant adeno-associated virus serotype 9–β5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of β5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9–β5i-injected mice. Mechanistically, Ang II upregulated β5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-β1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF. In summary, this study identifies β5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting β5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

“…The immunoproteasome has critical functions in the regulation of protein degradation, immune cell homeostasis, oxidative stress and cell apoptosis [13,14]. Recently, we showed that the β2i and β5i subunits are involved in the development of cardiac remodeling, atrial fibrillation and retinopathy, thus extending previous knowledge about the immunoproteasome [15][16][17][18]. Notably, subunit β5i was upregulated in the shoulder areas of symptomatic carotid plaques as compared with non-symptomatic plaques, suggesting a correlation between β5i activity and plaque instability [19].…”

“…It has been demonstrated to be 20‐ to 40‐fold more selective for the β5i subunit than the constitutive β5 subunit and other immunoproteasome subunits . Increasing studies indicate that inhibition of the β5i subunit by PR‐957 is promising for the treatment of inflammatory and autoimmune diseases, with limited side effects . Here we extended the therapeutic potential of PR‐957 and immunoproteasome inhibition in atherosclerosis; however, this needs further verification in other animal models.…”

“…Increasing studies indicate that inhibition of the β5i subunit by PR-957 is promising for the treatment of inflammatory and autoimmune diseases, with limited side effects [18,[53][54][55][56]. Here we extended the therapeutic potential of PR-957 and immunoproteasome inhibition in atherosclerosis; however, this needs further verification in other animal models.…”

“…It is well known that immune and inflammatory cells, including macrophages, T cells and dendritic cells, play an important role in the development and progression of atherosclerosis [23,24]. The immunoproteasome is expressed constitutively in immune cells, and can be induced in immune and non-immune cells upon exposure to pro-inflammatory stimuli such as viruses, angiotensin II and high salt, thus contributes to the regulation of immuno-inflammatory diseases, including viral myocarditis, hypertrophic remodeling, atrial fibrillation and vascular cell apoptosis [15,16,18,[25][26][27][28]. Here, the results presented showed that β5i was upregulated in the atherosclerotic plaques of eKO mice (Figure 1); genetic ablation or inhibition of β5i reduced lesional accumulation of apoptotic cells but enhanced MERTK-mediated efferocytosis, therefore inhibited necrotic core formation and atherosclerosis progression (Figures 2-4).…”

Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice

“…After 3 weeks of treatment, the mice were anesthetized by an intraperitoneal injection of 2.5% tribromoethanol (0.02 mL/g; Sigma-Aldrich, St. Louis, MO, USA) [20]. At the end of Ang II infusion, intracardiac pacing was performed in mice through the insertion of an eight-electrode catheter (1.1F, octapolar EP catheter, Scisense, London, Ontario, Canada) via the jugular vein and its advancement into the right atrium and ventricle [20].…”