免疫蛋白酶体是降解蛋白质的主要途径之一，β5i亚基是其激活和发挥功能的关键亚基。我们既往研究发现血管紧张素II（Ang II）可激活免疫蛋白酶体进而导致心肌重构，其中β5i催化亚基的表达和活性增高最显著。我们前期实验又发现应用β5i特异性抑制剂（PR-957）处理后可明显抑制Ang II诱导的心肌细胞肥大和纤维化，并抑制AKT和ERK信号通路，提示β5i在心肌重构中具有非常重要的作用。但其被激活及其促进心肌重构的病理生理机制并不清楚。本课题将在β5i亚基基因敲除、心肌特异性转基因小鼠及培养的细胞上，采用Ang II灌注和胸主动脉缩窄术诱导的心肌重构模型中，研究β5i亚基高表达的分子机制及其对心肌重构（包括肌细胞肥大、凋亡、炎症反应及纤维化）、心脏功能及负性调节蛋白表达水平的影响，并在心肌组织和细胞中阐明β5i亚基作用的病理生理机制，为寻找防治心肌重构的靶点提供新的实验依据。

The immunoproteasome represents the main mechanism of degradation of intracellular cytosolic and nuclear proteins, and the incorporation of β5i subunit is the critical step to promote its activation. Our previous study found that activation of the cardiac immunoproteasome promotes angiotension II-induced remodeling, and the protein expression and activity of β5i subunit was markedly up-regulated. Furthermore, our pre-experiment’s results also showed β5i specific Inhibitor (PR-957) treatment significantly prevented Ang II-induced cardiac hypertrophy and fibrosis, and inhibited the phosphorylation of AKT and ERK. However, the pathophysiological mechanism of β5i subunit activation and its promoting cardiac hypertrophy remain to be elucidated. This topic will study the molecular mechanism of β5i activation, the effect of β5i activation on cardiac remodeling (including cardiomyocyte hypertrophy, apoptosis, inflammation and fibrosis) and cardiac function and negative regulation protein in β5i gene knockout, cardiac-specific transgenic mice and in neonatal rat cardiomyocytes by Ang II infusion and thoracic aortic contraction (TAC) induced cardiac remodeling, and further investigate the molecular mechanism by which β5i mediating the above effects. Finally, we will clarify β5i activation induce cardiac remodeling and its molecular mechanism, and will provide new experimental evidence for looking for target to prevent cardiac remodeling.