冠脉内微粒抑制心肌梗死后心脏纤维化的作用机制研究

MP is commonly believed as an important messenger and mediator in pathophysiological processes. Our previous study has identified that abundance microparticles (MP) in the occlusive coronary. We discovered that MP in the occlusive coronary has the ability to improve cardiac function and reverse myocardial fibrosis. Further proteomics and bioinformatics researches identified anti-fibrosis proteins including Haptoglobin were elevated in those MP. However, the detail mechanism of those MP influenced myofibroblasts and meditate cardiac fibrosis was still unclear. In present research, we will take the advantages of proteomics technology, discover the underlying mechanism of the anti-fibrosis function of MP from thrombus aspiration. We will testify weather MP could inhibit ERK1/2 and p38 signaling pathway and influence the nuclear import of Smad proteins and hence regulate the cardiac fibrosis process. In summary, our present study is looking forward to investigate the cardio-protective effects of MP and offering new clues to the therapy of cardiac fibrosis and heart remodeling.

微粒（Microparticles，MP）是介导病理生理过程的重要信使。本课题组通过急性心肌梗死血栓抽吸血液组分研究发现，心梗患者阻塞的冠脉内的MP（O-MP）水平明显高于外周血的MP（C-MP）；动物实验发现O-MP可以显著抑制心脏纤维化；O-MP和C-MP的比较蛋白质组学研究显示O-MP内的Haptoglobin等抗纤维化蛋白表达明显上调。有关心肌梗死后冠脉内MP如何调控心脏纤维化及其分子机制尚不清楚。本课题将结合急性心肌梗死临床抽吸样品及蛋白质组学技术，探讨并验证心肌梗死患者冠脉内MP在心梗后心脏纤维化的作用及机制；明确冠脉内MP是否通过抑制ERK1/2、p38信号通路，影响TGF-β通路的Smad蛋白入核，调控心肌梗死后心脏纤维化。本课题研究将为心肌梗死后心脏纤维化的防治提供新的线索。

通过血栓抽吸获得的与梗塞相关动脉的血液是研究心肌梗塞局部血管微环境的良好材料。本研究中，我们旨在观察冠状动脉内微粒对心梗后心脏纤维化的影响，并探究在其中可能发挥作用的microRNA。我们从行急诊PCI的ST段抬高心梗患者中采集抽吸血和外周血，并采用超速离心法分离微粒。我们发现，与用PBS对照或外周微粒的大鼠相比，用冠脉内微粒治疗的大鼠在心梗后表现出更好的心脏功能。RNA微阵列分析表明，microRNA，尤其是miR-625-5p，可能在此过程中起作用。在小鼠心肌梗死模型中，补充miR-625-5p可抑制心脏成纤维细胞的增殖和心肌纤维化。Western blot表明，miR-625-5p的可能下游蛋白HMGA1在心梗后水平增高，并能够被miR-625-5p抑制。siRNA阻断HMGA1在体外降低了CTGF和TGF-β1水平。我们的研究结果表明，急性心梗患者的梗死相关动脉中的微粒可以抑制心肌纤维化并改善心脏功能，其过程由miR-625-5p和HMGA1介导。