mtDNA在糖尿病心肌细胞损伤中的作用及机制研究

Diabetic cardiomyopathy (DCM) is a specific myocardial disease caused by diabetes, and it is great harmful to human health due to the incidence of occult and complex pathological mechanism. Recently, the level of plasma cell-free mtDNA has recently emerged not only as a potential biomarker of aging, reflecting systemic inflammation, and cell death and acute trauma, and can induces an immune response via activation of TLR9 signaling pathway,which is closely related to cell damage. Yet the relationship between mtDNA and DCM is still poorly understood. In primary study, we found the levels of plasma mtDNA in diabetes patients are significantly higher than in healthy group, and diabetic cardiomyopathy patients has more than twice as high as people in diabetes, and we also found TLR9 expression is upregulated in myocardial cell of db/db mouse, so we suggest that mtDNA plays an important role in diabetic myocardial cell injury and may leading to the occurrence of DCM. To test this hypothesis, we will use the cultured myocardial cells and diabetes mice model, using a variety of technical means, from the cells, animals and clinical to investigate the important role of mtDNA in DCM and hope to provide a new theoretical basis for the treatment of DCM.

糖尿病心肌病（DCM）是由糖尿病引起一种特异性心肌疾病，因发病隐匿，病理机制复杂对人类健康危害极大。近年来，循环中线粒体DNA（mtDNA）的水平不仅可反映系统性炎症、细胞死亡和急性外伤程度，并且可通过活化TLR9信号通路诱导免疫反应，与细胞损伤发生密切相关。迄今对mtDNA与DCM的关系仍知之甚少。我们前期研究发现血浆mtDNA在糖尿病患者和DCM患者中显著升高，且DCM 患者mtDNA水平显著高于糖尿病患者，同时糖尿病心肌细胞损伤后TLR9表达上调，提示mtDNA在糖尿病心肌细胞损伤中起重要作用。为此，我们提出假说：糖尿病患者血浆中mtDNA可能通过TLR9 引起心肌细胞损伤，进而导致DCM的发生。为验证这一假说，我们将利用培养的心肌细胞和糖尿病小鼠模型，采用多种技术手段，从细胞、动物、临床等多方面探讨mtDNA在DCM发生中的重要作用，为DCM的治疗提供新的理论依据

血浆游离线粒体DNA（mtDNA）的水平不仅可反映系统性炎症、细胞死亡和急性外伤程度，并且可通过活化TLR9信号通路诱导免疫反应，与细胞损伤发生密切相关。糖尿病心肌病（DCM）是由糖尿病引起的一种特异性心肌疾病，因发病隐匿，病理机制复杂对人类健康危害极大。本项目旨在探讨血浆中mtDNA的水平能否作为反映糖尿病及糖尿病心肌病的疾病进展指标，以及mtDNA所致糖尿病心肌细胞损伤的作用机制。研究表明血浆mtDNA的水平在糖尿病（DM）患者和糖尿病心肌病（DCM）患者中显著升高，且DCM 患者mtDNA水平显著高于DM患者，Spearman相关性分析表明，在糖尿病心肌病患者中，mtDNA浓度与C反应蛋白（CRP）呈正相关性，mtDNA的水平可以作为反映患者是否伴有心肌细胞损伤的生物标志物。动物实验研究结果证实尾静脉注射外源性mtDNA能够导致糖尿病大鼠心肌细胞进一步损伤，TLR9-P38MAPK信号通路激活，而TLR9抑制剂氯喹（CQ）可以部分阻断此信号通路，并在一定程度上削弱mtDNA对糖尿病大鼠心肌细胞的损害。体外细胞实验进一步证实mtDNA能够通过TLR9，激活NFkB和p38MAPK通路，造成心肌细胞损伤，从而揭示mtDNA对心肌细胞损伤的机理。