心外膜脂肪组织TTP在病理性心肌肥厚发生发展中的作用及机制研究

病理性心肌肥厚是心律失常、心衰、心源性猝死的重要独立危险因素，探究其具体机制是心血管生物学的优先任务。心外膜脂肪与心血管疾病风险密切相关，其与下层心肌直接接触，共享冠状动脉供血，且分泌的多种脂肪因子可参与调节心血管稳态，其中脂肪因子FABP4与心脏改变如心肌肥厚、心功能障碍直接相关。前期研究证实，脂肪特异性敲除TTP可加重病理性心肌肥厚，RNA 结合蛋白TTP可以与FABP4 mRNA 结合并调节其表达。据此我们提出假说：脂肪特异性敲除TTP后，FABP4表达增加，继而FABP4通过旁分泌作用于心肌细胞，激活MEK/ERK信号通路，促进心肌肥厚。本研究拟利用脂肪特异性敲除TTP小鼠，小鼠主动脉缩窄术或皮下泵入AngII构建心肌肥厚模型，体外共培养脂肪细胞和原代心肌细胞，探究心外膜脂肪TTP在心肌肥厚发展中的作用及具体机制。本研究将有望为逆转病理性心肌肥厚、预防或治疗心血管疾病打开新思路。

Pathological cardiac hypertrophy is an important independent risk factor for arrhythmias, heart failure and sudden cardiac death. Exploring its specific mechanism is a priority task in the field of cardiovascular biology. Epicardial adipose tissue is closely related to the risk of cardiovascular diseases, which is in direct contact with the underlying myocardium and shares blood supply with the coronary artery. Moreover, various adipokines secreted can be involved in regulating cardiovascular homeostasis, among which adipokine FABP4 is directly related to cardiac changes such as cardiac hypertrophy and cardiac dysfunction. Previous studies have confirmed that adipose-specific TTP knockout can aggravate pathological cardiac hypertrophy, and RNA-binding protein TTP can specifically bind to FABP4 mRNA and regulate its expression. Therefore, we proposed a hypothesis that FABP4 expression is increased in epicardial adipocytes after TTP specific knockout in adipose tissue, and then FABP4 acts on cardiomyocytes through paracrine mode to activate MEK/ERK signaling pathway and promote cardiac hypertrophy. This study intends to use adipose specific TTP knockout mice to construct the pathological myocardial hypertrophy model by transverse aortic constriction or continuous pumping angiotensin II. Furthermore, we intend to coculture adipocytes and primary cardiomyocytes to explore the role of epicardial adipose tissue TTP in the development of pathological myocardial hypertrophy and its specific mechanisms. This study is expected to open up new ideas for reversing pathological cardiac hypertrophy and preventing cardiovascular diseases.