HMGB1在病毒性心肌炎内质网应激相关炎症中的作用及其分子机制

内质网应激（ER stress）是机体应对不利因素的重要病理生理反应，参与多种心血管疾病的发生发展。我们前期工作显示，柯萨奇病毒B3型（CVB3）诱导的小鼠心肌炎模型中，心肌ER stress IRE1通路及其相关炎症应答显著激活，并与心肌炎症密切相关，但其启动及调控机制尚不明了。我们发现CVB3感染可显著诱导HMGB1分泌并上调其受体TLR4表达，而下调HMGB1可显著削弱CVB3感染小鼠心肌IRE1通路及相关炎症，明显改善心肌炎。因此我们提出如下科学假设： CVB3感染后，心肌释放大量危险信号HMGB1，后者经TLR4受体激活心肌IRE1通路，并对其下游TRAF2-JNK-AP1，XBP1-FoxO/IKK-NF-kB等炎症通路进行调控，进而参与心肌炎发病。本研究不仅有望阐明病毒性心肌炎ER stress相关炎症的启动和调控机制，同时也可能为其防治提供新的靶点。

ER stress, an important pathophysiological processes against unfavorable factors, contributes greatly to a variety of cardiovascular diseases. Our previous data showed that IRE1 pathway of ER stress was obviously activated in CVB3-induced myocarditis and positively related to the severity of myocardial inflammaiton; however, its initiation and regulation mechanisms remain unclear. We showed that danger signal HMGB1 and its receptor TLR4 could be robustly induced in CVB3-infected cells, and downregulation of HMGB1 signficantly reduced heart IRE1 pathway and associated myocardial inflammation, led to alleviated viral myocarditis. Herein, we raised the scientific hypotheis as follows: By binding TLR4 receptor, HMGB1 released by CVB3-infected myocardium may initiate and regulate the downstream of inflammation-associated IRE1 pathway TRAF2-JNK-AP1, XBP1-FoxO/IKK-NF-κB in myocardial ER stress and consequently promote the proinflammatory cytokine expression and aggravate viral myocarditis. This study may elucidate the initiation and regulation mechanisms of ER stress in CVB3-infected myocardium, and may provide a potential target for prevention and therapy of viral myocarditis.