Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in Mice

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.

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 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

“…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]. The inducibility of AF was measured by applying a 5-s burst using an automated stimulator as described previously and recorded with a computer-based data acquisition system (GY6328B; Henan Huanan Medical Science and Technology, Co., Ltd., Zhengzhou, HA, CHN) [4,20]. A series of bursts were repeated three times after stabilization for 5 min.…”

“…Since atrial structural remodeling is a major risk factor for AF [4], we then examined the effect of LDN on atrial dilation in vivo. Echocardiography revealed that the Ang IIinduced dilation of the left atrium (LA) observed in vehicletreated WT mice was also attenuated in LDN-treated mice (Fig.…”

“…Increasing evidence has demonstrated that the renin-angiotensin system (RAS) plays a key role in the initiation and development of AF. AngII (angiotensin II) exerts its biological functions via the activation of angiotensin type 1 receptor (AT1R) [4]. The activation of AT1R stimulates several downstream mediators, including AKT/ERK, TGF-β/Smad, MAP kinases, NADPH oxidase, NF-kB, and hypoxia inducible factor-1alpha (HIF-1α), which are involved in vasoconstriction, fibrosis, inflammation, oxidative stress, and ion channel abnormalities [1,[5][6][7], Ang II-mediated inflammation and oxidative stress are thought to promote atrial fibrosis in AF [2,8,9].…”