Knockout of immunoproteasome subunit beta 2i ameliorates cardiac fibrosis and inflammation in DOCA/Salt hypertensive mice
Knockout of immunoproteasome subunit beta 2i ameliorates cardiac fibrosis and inflammation in DOCA/Salt hypertensive mice
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免疫蛋白酶体亚基 β 2i 的敲除可改善 DOCA/Salt 高血压小鼠的心脏纤维化和炎症
DOI：
10.1016/j.bbrc.2017.05.011
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发表时间：
2017
影响因子：
3.1
通讯作者：
Li Hui-Hua
中科院分区：
文献类型：
--
作者：
Yan Wen;Bi Hai-Lian;Liu Li-Xin;Li Nan-Nan;Liu Yang;Du Jie;Wang Hong-Xia;Li Hui-Hua
免疫蛋白酶体是真核细胞中的一种多催化蛋白酶复合物，在调节细胞的基本过程中起着关键作用。然而，免疫蛋白酶体亚基β 2 i在脱氧皮质酮醋酸酯（DOCA）/盐小鼠中调节心脏纤维化和炎症的作用仍然未知。对野生型（WT）和β 2 i敲除（KO）小鼠进行单肾切除术和DOCA/盐处理21天。血压测量采用尾袖法。通过超声心动图、苏木素-伊红（H&E）和马森三色染色检查心脏功能和重塑。采用实时荧光定量PCR和Western blot检测基因和蛋白的表达。21 d后，DOCA/盐处理显著上调心脏β 2 i mRNA和蛋白的表达。此外，DOCA/盐小鼠的收缩压和心脏重量/体重（HW/BW）比显着高于假手术组，而这些效应在β 2 i基因敲除小鼠中显着逆转。重要的是，DOCA/盐诱导的野生型心脏中的心脏纤维化、炎症和I型胶原、III型胶原、α-SMA、IL-1β、IL-6和TNF-α的表达被β 2 i敲除显著减弱。这些有益作用至少部分是由于IκBα/NF-κB和TGF-β1/Smad 2/3信号通路的抑制。总之，这些发现表明β 2 i敲除可改善DOCA/盐诱导的心脏纤维化和炎症，并且可能是高血压心脏病的新的潜在治疗靶点。
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 β2i in regulation of cardiac fibrosis and inflammation in deoxycorticosterone-acetate (DOCA)/salt mice remains unknown. Wild-type (WT) and β2i 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 β2i 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 β2i knockout mice. Importantly, DOCA/salt-induced cardiac fibrosis, inflammation and the expression of collagen I, collagen III, α-SMA, IL-1β, IL-6 and TNF-α in the wild-type hearts, which were markedly attenuated by β2i knockout. These beneficial effects were due, at least in part, to the inhibition of IκBα/NF-κB and TGF-β1/Smad2/3 signaling pathways. Collectively, these findings indicate that knockout of β2i ameliorates DOCA/salt-induced cardiac fibrosis and inflammation, and may be a novel potential therapeutic target for hypertensive heart diseases.