BAG3在血管平滑肌细胞表型转化中的作用及其分子机制

The phenotypic modulation of vascular smooth muscle cells (VSMCs) from differentiation to dedifferentiation is a critical feature of the onset of the vascular diseases such as hypertension. Myocardin plays a pivotal role in the process of VSMC differentiation and phenotypic transition.BAG3 is a member of BAG family.Recent studies imply an important role of BAG3 in cardiac diseases. Normal tissues seldom express BAG3, except for cardiomyocyte and skeletal muscle cells, but its expression is induced upon exposure to various stressful stimuli. For the first time, we found that BAG3 expression was increased with continued passages in cultured primary rat vascular smooth muscle cells (VSMCs). We also demonstrated that BAG3 expression was negatively related with VSMC marker genes. Using co-IP and GST pull down, we identified that BAG3 directly interacted with myocardin. These data implied that BAG3 may suppress differentiation of VSMCs via interaction with myocardin and promote abnormal proliferation. The current project aims to clarify the function of BAG3 in phenotypic transition of VSMCs and its potential mechanism. This project will provide potential target for prevention/treatment of vascular diseases such as hypertension.

正常血管平滑肌细胞（VSMC）高度分化，但是在高血压等血管疾病发生时，VSMC则向增殖表型转化。心肌素（myocardin）在平滑肌细胞分化和表型转化方面具有重要意义。BAG3 是共分子伴侣BAG 家族一员。最新研究表明BAG3 在心脏疾病中发挥重要功能。除心肌和骨骼肌外，正常组织很少表达，在应激情况下，BAG3 可被诱导表达。我们首次发现随传代次数增加，原代大鼠VSMCs 开始表达BAG3，并且BAG3 的表达水平与VSMC 收缩基因表达负相关。采用免疫共沉淀和GST pull down 鉴定出BAG3 与心肌素直接相互作用。结果提示BAG3 可能通过与心肌素相互作用而降低其转录活性，抑制VSMC 分化和血管收缩性，促进平滑肌细胞异常增殖。本项目拟阐明这一科学假设并探讨BAG3 在VSMC表型转化中的作用，为高血压等重大疾病的防治提供新的思路。

我们在已结题项目“BAG3在血管平滑肌细胞表型转化中的作用及其分子机制”的研究中，发现了AGEs通过提高BAG3的表达水平，可促进VSMCs增殖、迁移，BAG3促进VSMCs增殖、迁移是通过氧化应激反应起作用的；发现了BAG3在原代大鼠VSMCs分化型中低表达，未分化型中高表达，BAG3对大鼠VSMCs的促增殖作用依赖于TRAIL的表达，促迁移作用与TRAIL无关;此外，我们也发现了在VSMCs中，AGEs通过与CatD相互作用，抑制自噬溶酶体的降解，从而促进VSMCs增殖，AGEs能够促进VSMCs迁移，但不是通过CatD发挥作用；在项目执行过程中，我们进一步延伸了项目内容，获得了新的生长点，进一步发现了阿托伐他汀对AngII诱导的H9c2心肌细胞肥厚和SHR高血压诱导的心肌肥厚的保护作用。