NLRP3炎症小体-巨噬细胞M1/M2失衡在糖尿病小鼠脑心综合症中的作用及机制研究

脑心综合征为继发于神经系统疾患的新发心脏功能紊乱或原有损伤加重的特殊现象，是发病初期除原发病外的第一死因。糖尿病（DM）相关的心脏功能障碍较常见，DM状态是否加重脑心综合征尚不清楚。已知炎症反应与DM、脑卒中及心脏病关系密切，但其在DM合并脑卒中时对心脏功能影响的作用机制尚未明确。预实验显示，DM小鼠脑卒中后心脏功能受损加重，心肌纤维化增加；巨噬细胞明显浸润并呈不同极化状态；抑制NLRP3炎症小体可减轻心脏损伤并改善预后。那么，DM的脑心综合征中，巨噬细胞介导炎症反应的启动机制如何？研究表明，高糖上调TLR2/4表达并加重缺血性脑损伤；炎症小体增加并致DM小鼠心律失常。据此推测：DM合并脑卒中时，TLR2/4受体活化，NLRP3炎症小体激活，巨噬细胞极化失衡，促进心肌纤维化，加重心脏损伤。本项目拟通过体内外实验阐明TLR2/4-NLRP3炎症小体-巨噬细胞极化在DM脑心综合征中的作用机制。

Stroke-heart syndrome is a special phenomenon of new-onset or aggravation of cardiac dysfunction secondary to neurological disorders. It is the first cause of death in addition to the original disease at the beginning of stroke. Diabetes mellitus (DM) -related cardiac dysfunction is more common, and it is unclear whether DM aggravates stroke-heart syndrome. It is known that the inflammatory response is closely related to DM, stroke and heart disease, but the mechanism of its effect on heart function when DM is combined with stroke is not yet clear. Our pre-experiment showed that cardiac function of the DM mice was aggravated after stroke, and the myocardial fibrosis increased. Macrophage significantly infiltrated and showed different polarization states. Inhibition of NLRP3 inflammasome can reduce heart injury and improve prognosis. So, in the stroke-heart syndrome of DM, what is the initiation mechanism of macrophage-mediated inflammation? Studies have shown that high glucose up-regulates TLR2/4 expression and aggravates ischemic brain damage. NLRP3 inflammasome increase and cause arrhythmia in DM mice. Based on our latest findings and recent advancement in DM and stroke-heart syndrome, we hypothesize that when DM is combined with stroke, TLR2/4 receptors and NLRP3 inflammasome are activated and macrophage polarization imbalance which promote myocardial fibrosis and aggravate heart damage. To test this hypothesis, we plan to identify the mechanism of TLR2/4 - NLRP3 inflammasome - macrophage polarization in DM stroke-heart syndrome through in vivo and in vitro experiments.