热休克蛋白B3（HSPB3）对小鼠心肌肥厚的作用及机制研究

Cardiac hypertrophy is an important pathological process of cardiac remodeling and the common pathway for a variety of diseases such as hypertension, myocardial infarction, valvulopathy, congenital heart diseases to final heart failure. However, the mechanism of cardiac hypertrophy has not been fully elucidated. Previous studies have demonstrated that some kinds of small heat shock proteins involved in cardiac hypertrophy. As a member of small heat shock protein family, HSPB3 mainly exists in heart, and plays an important role in maintaining structure and function of cardiomyocyte. At present, we can’t find any study about the role and mechanism of HSPB3 on cardiac hypertrophy. This project is proposed to use cardiac-specific HSPB3 knockout mice and animal model of cardiac hypertrophy to study the effect and mechanism of HSPB3 on cardiac hypertrophy at the whole animal level. While in vitro, cultivated primary myocardial cardiomyocytes of SD rat infected by specific adenovirus vector to silence or overexpress HSPB3 are applied to create hypertrophic model of cardiomyocyte induced by angiotensin Ⅱ (Ang Ⅱ) to clarify the mechanism of HSPB3 on cardiac hypertrophy at cellular level. At last, we inhibit or activate the key downstream molecular of HSPB3 at cellular level to reverse the phenotype resulted by HSPB3 overexpression or silencing. In this project，We try to expound the effect and molecular mechanism of HSPB3 on cardiac hypertrophy and provide new target for prevention and treatment of cardiac hypertrophy and even heart failure.

心肌肥厚是心脏重构的重要病理过程之一，是多种疾病（如高血压、心肌梗死、心脏瓣膜病、先天性心脏病等）向心衰发展的重要通路。目前，心肌肥厚的发生发展机制尚未完全阐明。以往研究发现，多种小热休克蛋白参与心肌肥厚发生发展机制。HSPB3是小分子热休克蛋白家族成员之一，主要表达于心肌细胞，在维持心肌细胞结构和功能方面起着重要作用。目前，国内外尚无关于HSPB3对心肌肥厚的作用与机制的报道。本课题拟运用心脏特异性HSPB3基因敲除小鼠建立心肌肥厚模型；培养大鼠原代心肌细胞，利用腺病毒载体感染沉默或过表达心肌细胞HSPB3基因，血管紧张素Ⅱ（AngⅡ）刺激构建心肌细胞肥大模型，分别在动物水平和细胞水平阐明HSPB3对心肌肥厚的作用及分子机制。最后在细胞水平抑制或激活HSPB3下游调控心肌肥厚的关键分子以期能逆转HSPB3沉默或过表达导致的表型。本课题力图阐述HSPB3对心肌肥厚的影响及分子机制。

心肌肥厚是心脏重构的重要病理过程之一，是多种疾病（如高血压、心肌梗死、心脏瓣膜病、先天性心脏病等）向心衰发展的重要通路。目前，心肌肥厚的发生发展机制尚未完全阐明。以往研究发现，多种小热休克蛋白参与心肌肥厚发生发展过程。HSPB3是小分子热休克蛋白家族成员之一，主要表达于心肌细胞，在维持心肌细胞结构和功能方面起着重要作用。目前，国内外尚无关于HSPB3对心肌肥厚的作用与机制的报道。本课题运用心脏特异性HSPB3基因敲除小鼠建立心肌肥厚模型；培养大鼠原代心肌细胞，利用腺病毒载体感染沉默或过表达心肌细胞HSPB3基因，血管紧张素Ⅱ（AngⅡ）刺激构建心肌细胞肥大模型，分别在动物水平和细胞水平阐明HSPB3对心肌肥厚的保护作用。最后我们通过应用AKT特异性抑制剂（MK-2206）在分子水平证实HSPB3的抗心肌肥厚效应至少部分依赖于对AKT信号通路的抑制。本研究首次成功构建心脏特异性HSPB3基因敲除小鼠的主动脉缩窄致心肌肥厚模型；首次在大体动物水平及细胞水平证实HSPB3基因对病理性心肌肥厚的保护效应。首次在分子水平证实HSPB3对心肌肥厚的保护效应部分依赖于心肌肥厚刺激因素下对AKT信号通路的抑制作用。本课题为心肌肥厚及心衰治疗靶点的探索提供新的理论基础。