髓过氧化物酶与心房纤维化的关系及其致心房颤动机制研究

Studies have found that atrial fibrillation (AF) is associated with inflammation. However, it remains largely unknown that whether AF is the result of inflammation and that the specific inflammatory mediators that affect AF. Our previous small sample size of clinical research has found that myeloperoxidase (MPO) is an independent risk factor for atrial fibrillation, but this conclusion requires validation of a large sample volume data. According to correlational studies, we speculate that MPO may be involved in both atrial fibrillation occurrence by promoting atrial fibrosis in which balance between matrix metalloproteinases (MMPs) and matrix metalloproteinases inhibitor (TIMP) is broken and atrial fibrillation development by influencing atrial electrical conduction. In our study, plasma MPO levels were demonstrated to be associated with atrial fibrillation on basis of large sample size clinical data in the first place. Then, we observed that whether there were parallel amount of MPO between atrial and plasma and that MMPs/TIMP changes in atrial. Finally, we watched the direct effect of MPO on atrial fibrosis atrial fibrillation and the influence of MPO on atrial electrical conduction combining Langendorff and single atrial myocyte on the basis of atrial fibrillation model which was established by using wild type and MPO gene knockout mice. We confirmed the above hypothesis from three levels, namely system, organization and cells. Our research will clarify a brand new atrial fibrillation mechanism caused by MPO and provide new ideas for the early stage prevention and control of atrial fibrillation.

研究发现心房颤动(房颤)和炎症相关。然而房颤是否是炎症的结果，影响房颤的具体炎症介质仍有待探查。我们前期小样本量临床研究发现髓过氧化物酶(MPO)是引起房颤的独立危险因素，但这一结论需大样本量资料验证。我们据相关研究推测MPO可能通过打破基质金属蛋白酶/基质金属蛋白酶组织抑制剂(MMPs/TIMP)的平衡促进心房纤维化参与房颤发生，并通过影响心房电传导参与房颤维持。本课题首先利用大样本量临床资料，证实血浆MPO含量与房颤相关；其次观察MPO心房沉积量是否与血浆含量平行，及心房MMPs/TIMP变化；最后应用野生型和MPO基因敲除小鼠建立房颤模型，观察MPO对心房纤维化和房颤的直接作用，同时在模型基础上结合Langendorff和单个心房肌细胞观察MPO对心房电传导的影响，从整体-组织-细胞三个层次，证实上述假说。本课题将阐明一种全新的MPO致房颤机制，为房颤的早期防治提供新思路。

炎症与心房颤动（房颤）的发生密切相关。明显的炎症或亚临床的炎症状态与许多炎症细胞因子和趋化因子的上调有关，且有大量文献表明，炎症被认为是促进心房纤维化病理改变的最主要侵袭因素。而心房纤维化是房颤结构性重塑的标志，反过来也成为房颤持续性存在的基础。髓过氧化物酶（myeloperoxidase, MPO）主要表达于中性粒细胞的过氧化物酶，是一种重要的炎性介质，在各种纤维化疾病中起重要作用。本研究首先探讨了MPO与房颤的关系，研究表明血浆MPO浓度升高与房颤患者的病程和严重程度密切相关。在高脂血症（HC）大鼠缺血/再灌注模型上，MPO的活性与大鼠缺血/再灌注心肌组织损伤呈正相关，其中涉及分子信号通路包括NO/ cGMP信号转导通路和caspase-3炎症信号通路，后者可能与心脏损伤后的致纤维化信号途径激活密切相关。在此模型上外源性给予脂联素可降低HC大鼠缺血/再灌注心肌组织MPO含量和活性，提高缺血再灌注心脏功能，其治疗的分子机制与改善上述2个信号通路有关。本研究还探讨了炎症因子TNF-α致房颤机制，研究表明，TNF-α通过线粒体ROS途径快速增加了心房细胞内自发性钙释放活动，提升了致心律失常性触发活动的可能，抗氧化可能是治疗炎症相关房颤有效靶点。本研究证实MPO与房颤患者病情严重程度相关；MPO通过激活NO/ cGMP信号转导通路和caspase-3炎症信号参与心脏损伤后的纤维化修复过程；炎症因子致房颤作用可能与其增加心肌细胞内ROS水平所致的钙调节紊乱密切相关。