Knockout of immunoproteasome subunit β2i ameliorates cardiac fibrosis and inflammation in DOCA/Salt hypertensive mice

The immunoproteasome is a multicatalytic protease complex in all eukaryotic cells, which plays a key role in regulating essential cellular processes. However, the role of immunoproteasome subunit b2i in regulation of cardiac fibrosis and inflammation in deoxycorticosterone-acetate (DOCA)/salt mice remains unknown. Wild-type (WT) and b2i knockout (KO) mice were subjected to uninephrectomy and DOCA/ salt treatment for 21 days. Blood pressure was measured by the tail-cuff system. Cardiac function and remodeling were examined by echocardiography, hematoxylin-eosin (H&E) and Masson's trichrome staining. The gene and protein expressions were detected by quantitative real-time PCR, and Western blot analysis. After 21 days, DOCA/salt treatment significantly up-regulated the expression of b2i mRNA and protein in the hearts. Moreover, systolic blood pressure and heart weight/body weight (HW/BW) ratio were significantly higher in DOCA/salt mice than in sham groups, and these effects were markedly reversed in b2i knockout mice. Importantly, DOCA/salt-induced cardiac fibrosis, inflammation and the expression of collagen I, collagen III, a-SMA, IL-1b, IL-6 and TNF-a in the wild-type hearts, which were markedly attenuated by b2i knockout. These beneficial effects were due, at least in part, to the inhibition of IkBa/NF-kB and TGF-b1/Smad2/3 signaling pathways. Collectively, these findings indicate that knockout of b2i ameliorates DOCA/salt-induced cardiac fibrosis and inflammation, and may be a novel potential therapeutic target for hypertensive heart diseases.