1-磷酸鞘氨醇通过调节组蛋白去乙酰化酶2（HDAC2）及其受体途径改善心肌重构的作用及其机制研究

Myocardial remodeling includes the changes of myocardial structure, function and phenotype caused by a series of complex mechanisms. It is the important cause leading to the morbidity and death of heart failure and the methods of its therapy progress slowly till now. In recent years, the role of histone deacetylase 2(HDAC2) in myocardial remodeling through regulating chromatin remodeling obtains attention gradually. Recent evidence has demonstrated that sphingosine-1-phosphate(S1P) can inhibit the enzymatic activity of HDAC2 which is closely related with myocardial remodeling and S1P receptors play an important role in the cardiovascular system. Our preliminary study found that the level of S1P and the expression of all kinds of S1P receptors were significantly changed in the process of myocardial remodeling and S1P could attenuate cardiac hypertrophy in TAC mice as well as hypertrophic response induced by phenylephrine in H9C2 cells. This project will study the effects of S1P on myocardial remodeling through regulating HDAC2 in vitro and in vivo experiments and pick out the type of S1P receptor against myocardial remodeling in vitro, then using this S1P receptor knock-out mice to study the effects and mechanism of the S1PR in myocardial remodeling. This study could comprehensively evaluate the relationship between S1P and the development of myocardial remodeling, providing a theoretical basis for the prevention and treatment of myocardial remodeling and the development of new drugs.

心肌重构是由一系列复杂的机制造成的心肌结构、功能和表型的变化，是导致心力衰竭发病和死亡的重要原因，其治疗至今进展缓慢。近年来，通过组蛋白去乙酰化酶2（HDAC2）调节染色质重塑在心肌重构中的作用逐渐受到关注，有研究报道1-磷酸鞘氨醇（S1P）可以抑制HDAC2活性，且S1P受体在心血管系统也发挥重要作用。我们初步的研究发现S1P水平和S1P各型受体的表达在心肌重构过程中均发生显著变化，此外，S1P还可改善主动脉缩窄诱导的小鼠心肌肥厚，减轻苯肾上腺素诱导的心肌细胞系（H9C2）的肥大反应。本项目将在此基础上通过体内外实验，研究S1P通过调节HDAC2在心肌重构中的作用，并在细胞实验中筛出S1P抗心肌重构的受体，然后利用该受体敲除鼠探讨该S1P受体在心肌重构中的作用及机制，全面评价S1P与心肌重构发生发展之间的关系及其对心肌的保护效应，为心肌重构的防治和新药的开发提供理论基础。

心肌重构是由一系列复杂的机制造成的心肌结构、功能和表型的变化，是导致心力衰竭发病和死亡的重要原因，其治疗至今进展缓慢。近年来，通过组蛋白去乙酰化酶2（HDAC2）调节染色质重塑在心肌重构中的作用逐渐受到关注，有研究报道1-磷酸鞘氨醇（S1P）可以抑制HDAC2活性，且S1P受体在心血管系统也发挥重要作用。本项目的前期研究发现S1P有明显的抗心肌肥厚作用，但具体机制不清楚。通过构建S1PR1/2/3敲除基因鼠，动物实验与细胞实验相结合，进一步发现S1P介导的抗心肌肥厚作用主要是通过：1. S1P-HDAC2-KLF4信号通路，抑制HDAC2的活性，上调抗心肌肥厚因子KLF4的表达；3. S1P-S1PR2-ERK以及S1P-SPHK信号通路，抗心肌肥大；3. S1P-S1PR1-Akt-ERK1/2信号通路，减轻心肌内质网应激以及心肌凋亡；4. S1P-S1PR3-STAT3信号通路，减轻心肌纤维化；5. S1P-VEGF-VEGFR2-Akt信号通路，增加心脏微血管密度，延缓心肌肥厚病程。我们全面评价了S1P与心肌重构发生发展之间的关系及其对心肌的保护效应，为心肌重构的防治和新药的开发提供理论基础。