基于TLR4通路探讨肥大心肌细胞来源外泌体经Hsp90调节心肌炎症反应的机制

心肌肥大是多种心血管疾病并发症，严重危害人类健康。本课题组已证实，外泌体介导的炎症反应在心肌肥大发生发展中作用关键，但机制不详。资料表明，多种细胞来源Hsp90分布于外泌体内及其膜表面上。在预实验中，我们也发现：肥大心肌细胞来源外泌体富含Hsp90。众多研究还表明，Hsp90可调控TLR4信号通路，而后者与心肌炎症反应关系密切。因此，我们推测“肥大心肌细胞来源外泌体经携带的Hsp9参与调节TLR4信号通路，进而影响心肌炎症反应”是肥大心肌炎症反应调节的新机制。本项目拟应用透射电子显微镜、流式细胞仪、Western blot、Real-time PCR等技术，分析肥大心肌细胞来源外泌体携带的Hsp90的表达、分布特征，进一步从整体-器官-细胞层次探讨肥大心肌细胞来源外泌体携带的Hsp90对TLR4介导的心肌炎症反应的影响及分子机制。此研究将为心肌肥大的防治提供新思路。

Cardiac hypertrophy is a complication of several cardiovascular diseases, which seriously threaten the health of people. Our group has confirmed important role of exosome-mediated inflammatory response in the occurrence and development of cardiac hypertrophy, but the underlying mechanisms remain poorly understood. Recently, emerging data have indicated that Heat shock protein 90 (Hsp90) derived from various cell types is divided into two categories: exosomal Hsp90 and exosome surface Hsp90. In a preliminary experiment we further found that the expression of Hsp90 was significantly enhanced in hypertrophic cardiac myocyte-derived exosomes. Many studies have also shown that Hsp90 regulated Toll-like receptors 4 (TLR4) signaling pathway, whereas the latter is closely related to cardiac inflammatory response. Therefore, we propose a new mechanism of regulation of cardiac inflammatory response. We suppose that hypertrophic cardiac myocyte-derived exosomes transport Hsp90, which was capable of activating TLR4 signaling pathway in macrophages and contribute to inflammatory response in a TLR4 mediated manner. The aim of this study is to detect the expression and distribution of Hsp90 in exosomes secreted from hypertrophic cardiac myocytes using transmission electron microscope, flow cytometry, western blot and real-time PCR methods. Also, the effect of Hsp90 presented in exosomes on cardiac inflammation and its possible mechanism will be investigated at whole body, organ and cellular levels. This work has the potential to bring new ideas for the successful prevention and treatment of cardiac hypertrophy.