基于线粒体SIRT3/CyPD/mPTP通路研究丹参饮抗心肌缺血/再灌注损伤的作用机制

Acute myocardial infarction is one of the main causes of death in the world, timely revascularization is the main method to treat acute myocardial infarction. However, myocardial damage will occur following revascularization, known as ischemia/reperfusion injury (MIRI). How to reduce MIRI in the treatment of myocardial infarction is the clinical problem needs to be solved at present. We found that Danshen Decoction can reduce myocardial infarction area induced by I/R，and inhibite the opening of the mitochondrial permeability transition pore（ mPTP）. As we know：mitochondria plays an important role in MIRI, the opening of mPTP in the first few minutes of reperfusion determines the MIRI infarction area, Some studies report that the NAD+-dependent deacetylase SIRT3 deacetylates the regulatory component of the mPTP-cyclophilin D, decreases mPTP opening, improves mitochondrial function. Therefore, the research hepothesis is proposed that “Danshen Decoction could exert cardioprotective actions through inhibition the mPTP opening by SIRT3-mediated deacelylation of CyP-D”. In this study, we will explore the mechanism of Danshen Decoction against MIRI by observating the effect of Danshen Decoction on the degree of myocardial injure, oxidative stress ,myocardial cell apoptosis, mitochondrial structure and energy metabolism, mitochondrial membrane potential, mPTP opening, and expression and activity of CyPD and protein SIRT3 in vivo and isolated heart I/R model. It will provide scientific evidence for Danshen Decoction’s clinic use in the future.

急性心肌梗死是全世界最主要的死亡原因之一，及时血运重建是当前主要的治疗手段。但心肌缺血后血运重建可诱发心肌缺血/再灌注损伤（MIRI）。如何减少MIRI是目前临床亟需解决的问题。我们前期研究发现，丹参饮可以减少I/R心梗面积，并对线粒体膜通透性转换孔(mPTP)开放有抑制作用。结合线粒体在MIRI发病中的重要作用，I/R早期mPTP开放决定了I/R的梗死面积， SIRT3可以增加mPTP的组成部分CyPD去乙酰化，抑制mPTP开放、改善线粒体功能的文献报道，我们提出“丹参饮通过线粒体SIRT3/CyPD/mPTP通路改善MIRI”的科学假说。本课题拟从整体、离体器官/组织两个层面，观察丹参饮对I/R心肌损伤、氧化应激、细胞凋亡、线粒体结构和能量代谢、线粒体膜电位、mPTP开放、CypD和SIRT3蛋白表达及活性影响，探究丹参饮抗MIRI的作用机制，为丹参饮临床应用提供科学依据。

急性心肌梗死是全世界最主要的死亡原因之一，及时血运重建是当前主要的治疗手段。但心肌缺血后血运重建可诱发心肌缺血/再灌注损伤（MIRI）。如何减少MIRI是目前临床亟需解决的问题。目前尚无治疗MIRI的特效药物，本研究尝试运用中药经典方剂进行MIRI的防治研究。本课题应用心肌缺血/再灌注（I/R）大鼠模型，使用复方中药丹参饮药物预处理，观察丹参饮对于I/R心肌损伤、线粒体形态、功能、心肌细胞凋亡和对于心功能的影响。研究发现，I/R可以引起大鼠心肌损伤，线粒体的形态改变，线粒体通透膜转换孔的开放、线粒体的功能障碍，心脏功能和血流动力学障碍。使用丹参饮预处理，可以减少I/R大鼠的心肌梗死面积，改善大鼠的心功能和血流动力学指标，并可以减少心肌细胞凋亡，炎症反应和氧化应激，对线粒体的形态结构、线粒体通透膜转换孔的开放有部分抑制作用，并起到改善线粒体能量代谢的作用，具有心脏保护作用。但是研究未发现丹参饮预处理对大鼠I/R心肌线粒体SIRT3和CYP的水平的影响。另外我们还发现：应用具有活血化瘀作用的丹参饮，可以起到抑制急性心梗I/R大鼠急性期炎症反应、降低氧化应激的作用。为中医药防治MIRI提供了理论依据和临床基础。