表皮生长因子受体（EGFR）在肥胖性心肌病中的作用和机制研究

Obesity cause a variety of complications, including obesity cardiomyopathy (OCM), chronic inflammation and fibrosis mediated the pathological process of OCM. Although obesity has become a popular trend, the basic and clinic reaserch of OCM is still to be strengthened. Epidermal growth factor receptor (EGFR) is an important target for tumor therpy, recent studies have found that EGFR can mediate the insulin resistance, the process of atherosclerosis, cardiac hypertrophy and other chronic diseases. Our previous studies had found that orally giving EGFR inhibitors AG1478 and 542 significantly alleviated cardiac damage and accompanied by the decline of heart inflammatory reaction in high fat diet induced obese mice. In this project we propose the following hypothesis, EGFR mediated inflammatory response and cardiac injury induced by high fat, inhibiting EGFR can prevent OCM. In this project, we will confirmed high fat activated EGFR and the molecular mechanism of EGFR mediated high fat inflammation leading to cardiac cell injury in vitro; using high fat diet, cardiomyocyte EGFR knockout，ApoE-/- and cross-fertilize with ApoE-/- and EGFR-/- mice model to verify the effects of EGFR in OCM. This project will explain the effects and mechanism of EGFR in obesity cardiac inflammatory response and OCM, providing new targets for prevention and treatment of OCM.

肥胖引起多种并发症，包括肥胖性心肌病（OCM），其中慢性炎症和纤维化是介导肥胖性心肌病发生发展的重要病理过程。表皮生长因子受体（EGFR）是重要的肿瘤治疗靶点，近年研究发现EGFR还介导了多种慢性疾病的发生发展。我们前期研究发现：口服EGFR抑制剂AG1478和542在高脂饮食肥胖小鼠中显著缓解心肌损伤，并抑制心脏炎症反应；542可以抑制FFA诱导的体外心肌细胞炎症反应。因此本项目假设，EGFR介导了高血脂诱导的炎症反应和心肌损伤，抑制EGFR可以防治OCM。本项目中，我们拟在细胞层面确证高脂激活EGFR及EGFR介导高脂炎症反应从而导致心肌细胞损伤的分子机制；动物层面利用高脂饮食、心肌细胞EGFR敲除小鼠、ApoE-/-小鼠和ApoE-/-和EGFR-/-杂交小鼠模型验证EGFR在OCM中的作用。项目将阐明EGFR在肥胖心肌炎症反应和OCM中的介导作用和机制，为防治OCM提供新的靶点。

肥胖引起多种并发症，包括肥胖性心肌病（OCM），其中慢性炎症和纤维化是介导肥胖性心肌病发生发展的重要病理过程。表皮生长因子受体（EGFR）是重要的肿瘤治疗靶点，近年研究发现EGFR还介导了多种慢性疾病的发生发展。本项研究明确了EGFR在高脂血症/肥胖症相关心脏损伤的发病机理中起重要作用。利用高脂（HFD）喂养野生型（WT）和载脂蛋白E（ApoE-/-）敲除小鼠，结果显示小分子EGFR抑制剂AG1478和542可显著抑制肥胖引起的心肌损伤，并改善心肌的炎症反应、纤维化、细胞凋亡和功能障碍。体外H9C2细胞中，利用siRNA敲减EGFR后，棕榈酸（PA）诱导EGFR信号通路转导可被小分子EGFR抑制剂阻断。EGFR抑制减弱了PA引起的炎症反应和H9C2细胞凋亡。此外，我们发现PA诱导的EGFR激活被由上游TLR4和c-Src介导。这项研究证实了肥胖性心肌损伤与EGFR激活有关，并由TLR4 / c-Src介导。我们的数据表明EGFR可能是肥胖相关心血管疾病的治疗靶标。