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.
Keywords: AT1R associated protein; angiotensin II; atrial fibrillation; catalytic subunit β5; immunoproteasome; mice.