有氧运动通过HDAC4影响线粒体能量代谢改善梗死后心力衰竭机制研究

Aerobic exercise, as a rehabilitation program for heart failure, could improve symptoms and reduce mortality and re-hospitalization rate. However, the mechanism underlying the phenomenon remains to be determined. Recent studies reported that aerobic exercise can activate the adenylate activated protein kinase (AMPK) and promote phosphorylation of the histone deacetylase (HDAC) family. It has also been found that HDAC4 could participate in the mitochondrial metabolism through the myocyte enhancer 2 (MEF2) and the nuclear receptor nr4a1 pathway. In addition, our previous research showed that aerobic exercise could enhance cardiac function after infarction, increase exercise tolerance while improving the mitochondrial structure and function and the metabolism of glucose and lipid, and change HDAC4 expression in myocardium. Therefore, we hypothesized that aerobic exercise, by activating AMPK and phosphorylating HDAC4, could attenuate post-infarction heart failure and improve myocardial mitochondrial energy metabolism via the MEF2/nr4a1 pathway. To verify it, the HDAC4 knockout/over-expression mice will be used to establish models of post-infarction heart failure. After being interfered by aerobic exercise, techniques including PET/CT, echocardiography and molecular biology detection will be employed to assess cardiac function, energy metabolism and related signaling molecules. The study aims to elucidate the signal pathway through which aerobic exercise improves mitochondrial metabolism via HDAC4, and provide new therapeutic targets for heart failure.

有氧运动作为心力衰竭（心衰）的康复训练疗法，能改善其症状、减少死亡和再入院，但机制尚待明确。新近研究报道有氧运动激活腺苷酸活化蛋白激酶（AMPK）并促进组蛋白去乙酰化酶（HDAC）家族磷酸化，另有研究发现HDAC4能通过肌细胞增强因子2（MEF2）及核受体nr4a1途径参与线粒体代谢。而我们前期研究在动物水平发现：有氧运动能提升梗死后心功能，增加运动耐力，改善线粒体结构功能和糖脂代谢，并改变心肌HDAC4表达。由此我们提出假说：有氧运动激活AMPK，通过增加HDAC4磷酸化并经MEF2/nr4a1途径改善心肌线粒体能量代谢，从而延缓梗死后心衰进程。为求验证，我们拟运用HDAC4低/高表达小鼠建立梗死后心衰模型，有氧运动干预后利用PET/CT、心超及分子生物学技术，评估心功能、能量代谢及相关信号分子，旨在阐明有氧运动通过HDAC4改善心衰线粒体能量代谢的信号通路，并以此提出新的心衰治疗靶点。

有氧运动能够改善心力衰竭（心衰）症状、减少死亡和再入院，但机制尚不明确。既往研究显示有氧运动可激活腺苷酸活化蛋白激酶（AMPK）并促进组蛋白去乙酰化酶（HDAC）家族磷酸化，同时HDAC4能通过肌细胞增强因子2（MEF2）及核受体nr4a1途径参与线粒体代谢。因此，有氧运动是否可能通过AMPK-HDAC4-MEF2/nr4a1这一通路改善心衰线粒体能量代谢值得探索和验证。本课题探究了运动对糖酵解、葡萄糖有氧氧化以及脂肪酸β氧化代谢途径中关键催化酶mRNA及蛋白表达的变化，研究了HDAC4对能量代谢的作用及相关机制，通过ChIP分析了MEF2a与GLUT1的结合情况以及其中的表观遗传学变化，运用HDAC4抑制剂研究了其对心衰小鼠心功能、心脏对葡萄糖摄取以及对心肌细胞舒缩功能的影响，并采用液相色谱-质谱方法对小鼠心肌蛋白表达谱进行了鉴定和定量分析。最终研究证实了运动通过抑制 HDAC4 和上调 GLUT1 表达改善心衰小鼠的心脏功能和葡萄糖代谢，揭示了有氧运动在心肌梗死诱发心衰的背景下所引起的以PDC蛋白和PDKs的表达同时下调为特征的蛋白质组学变化。研究为有氧运动改善心梗后心衰提供了理论支持，为有氧运动改善心衰的机制提供了新的系统认识，为心衰的新型药物干预和开发提供了可参考的新的启示。