Immunoproteasome Subunit β5i Promotes Ang II (Angiotensin II)-Induced Atrial Fibrillation by Targeting ATRAP (Ang II Type I Receptor-Associated Protein) Degradation in Mice.
HYPERTENSION(2019)
摘要
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, 5i (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. 5i KO (5i 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 9-5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of 5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9-5i-injected mice. Mechanistically, Ang II upregulated 5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-B signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-1/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 5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting 5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.
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关键词
angiotensin II,AT1R associated protein,atrial fibrillation,catalytic subunit 5,immunoproteasome,mice
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