GSK-3β通过调控NLRP3炎性复合体的活化介导心肌电重构的作用机制

NLRP3 inflammasome-mediated immunal inflammatory response is involved in the pathological process of cardiac remodeling, but its role and molecular mechanisms in cardiac electrical remodeling has not been elucidated. Our preliminary results showed that: glycogen synthase kinase-3β (GSK-3β) regulated NLRP3 inflammasome activation and IL-1β secretion by catalyzing the glycosylation of ASC substrate. Our hypothesis is that GSK-3β is involved in the activation of NLRP3 inflammasome following myocardial infarction, and subsequently causes the IL-1β release leading to the occurrence of cardiac electrical remodeling. Our goal in this grant application is based on both in vivo and in vitro model of myocardial ischemia: 1) to explore the activation mechanism of GSK-3β in cardiac remodeling; 2) to show the molecular mechanism involved in GSK-3β mediated activation of NLRP3-inflammasome in cardiac remodeling; 3) to investigate the effects of GSK-3β on cardiac ion channel. This study will elucidate the roles of GSK-3β in control of cardiac electrical remodeling via NLRP3-inflammasome activation. The conculsion from this grant is to provide a new target for the prevention and treatment of cardial remodeling.

NLRP3 炎性复合体（inflammasome）介导的免疫炎症反应参与心肌重构的病理过程，但其在心肌电重构中的作用和分子机制尚未阐明。课题组前期工作发现：糖原合成酶激酶-3β（glycogen synthase kinase-3β，GSK-3β）可以通过糖基化ASC蛋白调控NLRP3炎性复合体的活化从而调节IL-1β的释放。由此提出假说：GSK-3β通过调控NLRP3炎性复合体的活化介导心肌电重构的过程。本课题拟在离体和在体心肌缺血模型上研究：1）GSK-3β在心肌重构中活化的特征和作用机制；2）GSK-3β调控心肌重构中NLRP3炎性复合体活化的分子机制；3）GSK-3β对心肌离子通道作用的分子机制。本课题试图从免疫炎症反应参与心肌电重构的角度，解释心肌损伤后心肌重构的分子机制，为心律失常的防治提供新思路和新靶点。

心肌梗死是心血管疾病中常见的高发病症，在全球范围内发病率均呈增高趋势，成为全球死亡和致残的主要原因。尽管目前治疗心血管疾病的药物和手段有多种，死亡率有所下降，但心源性猝死的比重却持续增加。因此，寻求新的治疗靶点，探索其发生机制，减少心源性猝死的死亡率，成为目前研究的热点。本课题主要研究内容有：①糖原合成酶激酶-3（GSK-3β）参与心肌重构中NLRP3炎性小体活化的分子机制；②GSK-3β对心肌梗死后心肌细胞离子通道电流的影响；③GSK-3β影响心肌梗死后整合素相关蛋白（CD47）表达变化的分子机制；④Caspase-1影响心肌梗死后缝隙连接蛋白43（Cx43）表达的分子机制。研究结果表明：①心肌梗死后，GSK-3β通过与ASC蛋白结合并影响ASC的磷酸化而参与心肌成纤维细胞NLRP3炎性小体的活化和IL-1β的分泌，并通过旁分泌作用进而调控心肌细胞的凋亡和焦亡；②GSK-3β参与心肌梗死大鼠内向整流钾通道Kir2.1蛋白表达的降低；③GSK-3β通过激活NF-κB信号通路调控心肌梗死后CD47蛋白表达的上调；④Caspase-1通过IL-1β/p38MAPK信号通路调控心肌梗死后Cx43蛋白表达的降低并减少细胞间的通讯连接。本课题从免疫炎症反应角度探讨心肌梗死后心肌重构和心律失常发生的分子机制，为缺血性心脏疾病的防治提供新思路和新靶点。