FFAR2对心肌肥厚的影响及机制

We found out that the expression of free fatty acid receptor 2(FFAR2, a member of FFAR family) was upregulated in cardiac hypertrophy when we studied the relationship between adipose triglyceride lipase(ATGL) and cardiac hypertrophy. Other studies showed that the activation could elicit the increase of triglyceride(TG) synthesis and the inhibition of lipolysis in adipose cells and hepatocytes,and induced inflammatory reaction. However, the dysfunction of lipid as well as inflammation in cardiomyocytes can accelerate the development of cardiac hypertrophy. Fourthermore, in our preliminary experiment, the activation of FFAR2 could induce hypertrophy and the increase of TG in neonatal rat cardiomyocytes. So we hypothesized that the activation of FFAR2 might result in the dysfunction of lipid and inflammation reaction of cardiomyocytes to promote the development of cardiac hypertrophy. First of all, the effect of FFAR2 on cardiac hypertrophy need to be confirmed both in vitro and vivo and in transgenic mice. And then we aimed to gain further insight into the mechanisms for resulting in hypertrophy, including lipid metabolism and inflammatory reaction. The key enzymes for TG synthesis such as glycerol-3-phosphate acyltransferase 1(GPAT1) and sn-1,2-diacylglycerol acyltransferase 1(DGAT1), and the key enzymes for lipolysis such as ATGL and hormone-sensitive lipase were studied in the activation of FFAR2. Another important research about FFAR2 is that whether it can induce inflammatory reaction in cardiomyocytes and the signalling pathways are also studied. From the above, we can find out whether FFAR2 involves in cardiac hypertrophy, and the mechanisms also would be preliminarily clarified. This study might provide a new strategy for the treatment of cardiac hypertrophy and heart failure.

在研究甘油三酯脂肪酶（ATGL）与心肌肥厚关系的过程中我们发现，心肌肥厚时FFAR2明显上调，一个游离脂肪酸受体家族成员。有研究显示，FFAR2可促进脂肪细胞、肝细胞等甘油三酯（TG）合成，并抑制分解，此外也促进炎症反应；而心肌脂质代谢异常及炎症反应与心肌肥厚有关。我们的预实验进一步表明，FFAR2的激活可在体外诱导心肌细胞肥厚，并有TG增加，因此提出假说：FFAR2能够促进心肌肥厚形成，这一作用可能与其扰乱心肌脂质代谢和促进炎症反应有关。本课题拟在体内外心肌肥厚模型及转基因小鼠中研究FFAR2是否具有促肥厚作用，并探讨机制，包括可能对TG合成关键酶GPAT1和DGAT1以及分解关键酶ATGL和HSL的影响及意义。FFAR2是否促进心肌细胞炎症反应及信号通路是另一项重要研究内容。本研究可阐明FFAR2是否具有促心肌肥厚的作用及机制，可能为心肌肥厚及心衰防治提供新的思路和药物作用的新靶点。

交感神经和肾素-血管紧张素系统的过度激活在心肌肥大和心力衰竭中扮演重要角色，目前能够抑制心肌肥大，进而改善心衰预后的药物也主要为上述两个系统的抑制剂；然而治疗效果仍然不能令人满意。游离脂肪酸受体2（FFAR2）主要调节能量代谢以及免疫功能，这两方均与心肌肥大有关。本课题研究发现：（1）FFAR2促进心肌肥大的形成：在心肌肥大时FFAR2表达上调；此外，我们采用FFAR2过表达、激动剂等多种技术手段证明FFAR2的过渡激活促进心肌肥大的形成。在整体条件下，FFAR2拮抗剂GLPG0974可显著抑制腹主动脉缩窄诱导的大鼠心肌肥大。这些结果表明，FFAR2参与了心肌肥大的形成。（2）FFAR2促进心肌肥大的机制：我们发现，参与心肌肥大过程两个重要转录因子GATA4和STAT3功能明显提高，主要体现在：GATA4的Ser105位点可被FFAR2明显增强，并且报告基因分析显示其转录活性也显著增加；STAT3两个重要磷酸化位点Tyr705和Ser727也可被明显提高，报告基因分析其活性显著上调。这两个转录因子功能的提高与FFAR2激活MAPK-ERK1/2有关。此外，我们对FFAR2促进脂质聚集以及对炎症因子表达的影响也均进行了探讨。通过本课题的研究，阐明了FFAR2与心肌肥大的关系，对促进心肌肥大的机制也进行了相应的探讨。有关成果对以FFAR2为靶点的药物研发具有重要意义。