乙醛脱氢酶2调控NLRP3炎症小体在重症急性胰腺炎导致心肌损伤中的作用及机制研究

Severe acute pancreatitis (SAP) is a critical disease subsequent to acute pancreatitis complicated with multiple organ dysfunction. SAP-induced myocardial injury and cardiovascular decompensation is the complication with the highest mortality in acute pancreatitis. Aldehyde dehydrogenase 2 (ALDH2) is one of the key enzymes of human alcohol metabolism pathway. Recently, ALDH2 has been identified as a key cardioprotective protein for myocardial injury caused by ischemia. Previous studies showed that myocardial reactive oxygen species (ROS) leads to the increase of reversible inhibition of ALDH2 activity, and ALDH2 could reduce cardiomyocyte apoptosis by suppressing PINK1/Parkin–dependent mitophagy mediated by ROS. Our preliminary experiments showed that SAP could induce the increase of ROS production in cardiac myocytes of ALDH2-/- mice, and then induce the activation of NLRP3/ASC/Caspase-1 inflammasome signal pathway, which suggesting that ALDH2 is one of the key regulatory proteins involved in ROS-induced NLRP3 inflammasome activation. Further research of animal and cell experiments should be performed to classify the molecular mechanism of ALDH2 on myocardial injury caused by SAP and provide a new perspective for the prevention and treatment strategies based on ALDH2 gene with a high mutation rate of more than 30% in Chinese population.

重症急性胰腺炎（SAP）是急性胰腺炎并发多脏器功能损害的急危重症，心肌损伤及心血管失代偿是其死亡率最高的并发症。乙醛脱氢酶2（ALDH2）是人体内酒精代谢的关键酶之一，近年来发现ALDH2是缺血性心肌损伤中心肌保护的关键靶点。前期研究发现心肌活性氧（ROS）的增加导致ALDH2活性的可逆性抑制，而ALDH2通过调控ROS介导的PINK1/Parkin依赖的线粒体自噬通路激活，减少心肌细胞凋亡。预实验提示SAP导致ALDH2-/-小鼠心肌细胞ROS生成明显增加，并诱导NLRP3/ASC/Caspase-1炎症小体信号通路激活，推测ALDH2是SAP导致的心肌损伤中ROS诱导NLRP3炎症小体活化的关键调控蛋白之一。我们拟通过动物和细胞实验深入探讨ALDH2影响SAP导致心肌损伤的分子生物学机制，基于我国人群ALDH2基因30%以上高突变率，本研究将为我国SAP心肌损伤的防治策略提供新的视点。

重症急性胰腺炎（SAP）是急性胰腺炎并发多脏器功能损害的急危重症，心肌损伤及心血管失代偿是其死亡率最高的并发症。乙醛脱氢酶2（ALDH2）是人体内酒精代谢的关键酶之一，近年来发现ALDH2是缺血性心肌损伤中心肌保护的关键靶点。ROS大量产生是AP早期的主要病理改变之一，在SAP病情进展过程中发挥着重要作用。胰腺是富含脂质的消化腺，ROS的大量产生会引起胰腺组织脂质过氧化，进而可能导致脂质过氧化终末代谢产物毒性醛类的生成增加。基于脂质过氧化在AP中重要的病理作用，ALDH2作为代谢毒性醛类的关键酶是否参与调控AP胰腺损伤发生发展过程是亟待揭示的科学问题，这将有助于AP新治疗靶点的发现。本项目研究中通过动物和细胞实验深入探讨AP胰腺组织中毒性醛蓄积情况以及ALDH2对胰腺滤泡细胞损伤的保护作用及机制，并发现一种参与心肌保护的小分子ALDH2活性激活剂在改善脏器损伤，提高生存率方面具有重要作用，主要与抑制AKT磷酸化与调控细胞凋亡信号通路相关。基于我国人群ALDH2基因30%以上高突变率，本研究将为我国SAP致脏器损伤的防治策略提供新的视点。