AMPK在曲美他嗪促心肌细胞增殖中的作用及机制研究

Cardiomyocyte proliferation is the main source of endogenous myocardial regeneration, but the proliferation ability of adult cardiomyocytes is very low. The rapid decrease in proliferation of cardiomyocyte after birth is related to the change of energy metabolism from glucose to fatty acid. Previous studies using trimetazidine (TMZ) showed that inhibition of fatty acid metabolism by TMZ could significantly promote the proliferation of cardiomyocyte and reduce AMPK phosphorylation. AMPK is a key signal in the process of myocardial cell proliferation, and its downstream pathways (p53-p21 and Hippo-Yap) also play an important role in the proliferation of cardiomyocyte. Therefore, we proposed to assume that TMZ promoted the proliferation of cardiomyocyte by regulating the transformation of fatty acid-glucose metabolism, so as to repair the myocardium of MI. AMPK is the induction kinase of this transition, and p53-p21 and Hippo-Yap signaling pathways are the downstream signals of AMPK. This project intends to adopt the pedigree tracking mouse system and live cell workstation and other advanced means to study the effect and mechanism of TMZ on myocardial proliferation after birth, so as to promote endogenous myocardial regeneration in mice after myocardial infarction and gradually achieve clinical transformation.

心肌细胞增殖是内源性心肌再生的主要来源，但成年心肌细胞增殖能力极低，如何诱导其增殖成为目前的研究热点。心肌细胞出生后增殖能力迅速减退与其能量代谢由葡萄糖向脂肪酸代谢转换相关。前期我们用药物曲美他嗪（TMZ）进行研究，显示了TMZ抑制脂肪酸代谢可显著促进心肌细胞的增殖，同时AMPK磷酸化水平降低。而AMPK是能量代谢感受激酶，是心肌细胞增殖过程中的关键信号，且其下游通路（p53-p21、Hippo-Yap）在心肌细胞增殖中也发挥重要作用。故我们提出设想TMZ通过调控脂肪酸-葡萄糖代谢的转换促进了心肌细胞增殖，达到修复MI心肌的作用；AMPK是该转变的感应激酶；p53-p21和Hippo-Yap信号通路是AMPK发挥作用的下游信号。本项目拟采用谱系追踪小鼠系统和活细胞工作站等先进手段，通过研究TMZ在出生后对心肌增殖的作用和机制，以期达到促进心肌梗死后小鼠的内源性心肌再生以逐步实现临床转化。

心肌细胞增殖是内源性心肌再生的主要来源，但成年心肌细胞增殖能力极低，如何诱导其增殖成为目前的研究热点。心肌细胞出生后增殖能力迅速减退与其能量代谢由葡萄糖向脂肪酸代谢转换相关。前期我们用药物曲美他嗪（TMZ）进行研究，显示了TMZ抑制脂肪酸代谢可显著促进心肌细胞的增殖，同时ROS水平显著降低。ROS水平增加，导致DNA损伤增加，并且在抑制心肌细胞增殖中也发挥重要作用。故我们提出设想TMZ通过调控脂肪酸-葡萄糖代谢的转换促进了心肌细胞增殖，达到修复MI 心肌的作用；脂肪酸代谢产生大量的ROS，ROS产生导致DNA损伤，DNA损伤增加抑制了心肌细胞增殖，而TMZ抑制脂肪酸代谢，促进了葡萄糖代谢会降低ROS的产生，减少DNA损伤，从而促进心肌细胞增殖。本项目拟采用谱系追踪小鼠系统和活细胞工作站等先进手段，通过研究TMZ在出生后对心肌增殖的作用和机制，以期达到促进心肌梗死后小鼠的内源性心肌再生以逐步实现临床转化。