免疫蛋白酶体亚基β2i在心肌重构中的作用及分子机制研究

Cardiac remodeling is a major cause of heart failure and death. The ubiquitin-proteasome system plays a key role in myocardial protein degradation. The immunoproteasome, as an induced form of the proteasome, is involved in inflammation-related diseases. Our previous study showed that the immunoproteasome subunit β2i regulated the development of atrial fibrillation，but its role in Angiotensin II (Ang II) and transverse aortic constriction (TAC)-induced cardiac remodeling is unclear. Recently, we found that protein expression of β2i was significantly increased in Ang II or TAC-treated cardiomyocytes and heart tissue. Knockdown of β2i mainly reversed Ang II-induced cardiac dysfunction, cardiomyocyte hypertrophy and fibrosis. However, the molecular mechanism of β2i in regulating cardiac remodeling was not yet fully understood. In this study, we aimed to investigate the molecular mechanism of up-regulation of β2i expression, pathophysiological mechanisms of β2i in cardiac remodeling, target proteins of β2i and their binding domain in Ang II or TAC induced cardiomyocytes and heart tissue. Finally, it provides a scientific basis for molecular mechanism of cardiac remodeling and a new therapeutic target.

心肌重构是导致心力衰竭和死亡的主要病因之一。泛素-蛋白酶体系统是调节心肌蛋白质降解的主要通路。免疫蛋白酶体是蛋白酶体的一种诱导形式，参与炎症相关性疾病。申请人既往研究表明免疫蛋白酶体亚基β2i参与心房颤动的发生，然而β2i在血管紧张素II（Ang II）和主动脉结扎（TAC）诱导的心肌重构中的作用不清楚。申请人前期研究发现β2i蛋白表达在Ang II或TAC处理的心肌细胞和小鼠心肌组织中明显增高。敲除β2i可显著改善Ang II诱导的心功能减低，抑制心肌肥大和纤维化，仍需研究β2i调节心肌重构的分子机制。本课题拟在Ang II和TAC诱导的小鼠心肌重构模型中，应用β2i敲除小鼠及体外细胞培养模型，探讨心肌中Ang II或压力负荷上调β2i表达的分子机制；阐明β2i调节心肌重构的病理生理机制；鉴定β2i作用的靶蛋白及其调控机制。最后为阐明心肌重构发生的分子机制及筛选新的治疗靶点提供科学依据。

心肌重构是导致心力衰竭和死亡的主要病因之一。泛素-蛋白酶体系统是调节心肌蛋白质降解的主要通路。免疫蛋白酶体是蛋白酶体的一种诱导形式，参与炎症相关性疾病。申请人既往研究表明免疫蛋白酶体亚基β2i参与心房颤动的发生，然而β2i在血管紧张素II（Ang II）诱导的心肌重构中的作用不清楚。经进一步研究，我们发现免疫蛋白酶体β2i 表达和活性在血管紧张素 II处理的心肌重构的小鼠心脏及高血压心肌重构患者的血清中显著增高。敲除β2i 抑制 Ang II诱导的心肌重构、纤维化、炎症反应，相反β2i 过表达加重这一效应。机制上发现β2i通过促进泛素化PTEN的降解，激活AKT/ERK信号通路从而导致心脏肥大，过表达PTEN抑制逆转β2i介导的心肌肥厚。综上所述,本研究明确了β2i 靶向 PTEN调节心肌重构的新生物学作用，为治疗高血压心肌重构的新提供新思路。