血糖波动通过上调ROS诱导心房心肌细胞焦亡促进心房纤维化的机制研究

Myocardial fibrosis is a characteristic pathological change of diabetic cardiomyopathy. Most studies have focused on the pathological mechanism of hyperglycemia induced myocardial fibrosis. Recent large epidemiological and clinical studies have suggested that enhanced blood glucose control increases the occurrence of diabetic cardiovascular events. Our previous studies have found that endoplasmic reticulum stress can induce atrial myocardial apoptosis and fibrosis. Pyroptosis is a new type programmed cell death between apoptosis and necrosis, IL-1β and other inflammatory mediators were released by pyroptosis would further aggravate the pyroptosis. IL-1β is an early protruding inflammatory mediator of diabetic cardiomyopathy and involved in the development of myocardial injury and fibrosis. The present study is proposed to investigate whether blood glucose fluctuations promote the incidence of cardiac fibrosis by inducing atrial myocardial pyroptosis caused by upregulation of ROS level, through both of the cells (atrial myocardial and HL-1 cells) and the animal models (wild-type and caspase-1 knockout SD rats). This study exploring the mechanism of the pathogenesis and development of the diabetic cardiomyopathy may provide a new strategy of the therapy and prevention.

心肌纤维化是糖尿病心肌病变的特征性病理改变，既往多数研究将目光聚焦于高血糖致心肌纤维化的病理机制。近期大型的流行病学调查及临床研究提示强化血糖控制造成的血糖波动增加了糖尿病性心血管事件的发生。申请人前期研究发现内质网应激可引起心房心肌细胞凋亡而致心房纤维化。细胞焦亡是介于凋亡和坏死之间的一种新的细胞程序性死亡方式，细胞焦亡所释放的IL-1β等炎症因子将进一步加重细胞焦亡，而IL-1β是糖尿病心肌病早期突出的炎性介质，参与心肌细胞损伤及心肌纤维化发生发展。本课题拟通过原代心房心肌细胞、HL-1心肌细胞株及血糖波动野生型、caspase-1基因敲除SD大鼠，分别从细胞和动物水平揭示血糖波动诱导和加重氧化应激，上调ROS介导炎症小体激活，启动心房心肌细胞焦亡，最终引起或促进糖尿病性心房纤维化形成的机制，从而为糖尿病患者心肌病变的发生发展提供新的研究和防治思路。

糖尿病心肌纤维化是糖尿病心肌病的特征性病理改变，氧化应激上调ROS诱导心肌细胞凋亡是致糖尿病心肌纤维化的关键因素，而血糖波动诱发心肌细胞焦亡加重了ROS介导的糖尿病心房纤维化过程。本研究通过葡萄糖波动组心房心肌细胞ROS水平上调和细胞焦亡特征性物质的表达增高，证实血糖波动可上调ROS并促进心房心肌细胞焦亡。通过caspase-1抑制剂抑制血糖波动组心房心肌细胞炎症小体激活，证实ROS通过激活炎症小体的激活导致心肌细胞焦亡。通过不同血糖状态SD大鼠心房纤维化的发生情况，证实血糖波动可诱导并加重心房纤维化的发生。通过caspase-1基因敲除与野生型SD大鼠的比较，证实血糖波动caspase-1基因敲除SD鼠心房心肌细胞ROS上调但无心肌细胞焦亡，且心房纤维化发病率低，证实血糖波动上调ROS通过诱导心房心肌细胞焦亡促进心房纤维化的发生发展。最终，我们从细胞水平和动物水平，证实露于血糖波动中的心房肌细胞线粒体将产生过量的ROS，ROS通过激活caspase-1酶诱导心房心肌细胞发生焦亡，同时释放出炎性因子IL-1β和IL-18等，加重炎症反应，焦亡的心房心肌细胞参与并促进了心房重构及心房纤维化的发生发展。对血糖波动诱导心房心肌细胞焦亡的研究将打开糖尿病心肌纤维化发生发展机制的新思路，为疾病的预防和治疗提供新的策略。