基于ALCAT1-心磷脂病态重构-线粒体自噬通路探讨脓毒症心肌病的重构/逆重构机制

Septic cardiomyopathy (SCM) is the main cause of both the death of septic patients and the readmission of survivors, however, the pathogenesis, especially the adaptive mechanism of reversing SCM in survivors, is still unknown. Our previous studies suggested that endoplasmic reticulum stress in the early stage of SCM induce autophagy resulting in removal of damaged mitochondria and heart protection, but the couple relationship between endoplasmic reticulum and mitochondria is not fully clear yet. Meanwhile, Acyl-CoA lysocardiolipin acyltransferase-1 (ALCAT1) localized in mitochondria-associated endoplasmic reticulum membrane can cause cardiolipin pathological remodeling which is the common pathological phenomenon shared by several cardiomyopathies, but there is little related study unfortunately. Based on these findings, we hypothesize that sepsis upregulte the level of ALCAT1, lead to CL pathological remodeling and result in SCM finally; then, pathological CL translocate to the outer membrane of mitochondria and promote endoplasmic reticulum stress and mitophagy which is helpful in removal of damaged mitochondria and reverse of SCM. So, we will firstly observe the effects of lipopolysaccharide on the level of ALCAT1 and CL pathological remodeling, and the link between the effects and the disorders of mitochondria structure and function, and myocardial remodeling ultimately, in vitro and in vivo. Then, we will observe the influence of translocation of pathological CL on mitophage and reverse of SCM. From the view of CL remodeling, the present proposal will explore the remodeling mechanism of SCM in the early stage and the reversing mechanism of survivors in the late stage. The findings will provide novel concept and control strategy to interpret and handle sepsis and the related multiple organ dysfunctions.

脓毒症心肌病（SCM）是造成脓毒症患者死亡和存活者再入院的主要原因，发病机制不明。我们前期发现，SCM早期内质网应激，经自噬清除受损线粒体可保护心功能，但内质网-线粒体偶联关系还有待深入。位于线粒体相关内质网膜的心磷脂酰基转移酶1（ALCAT1）可导致心磷脂（CL）病态重构，是多种心肌病的共有病理现象，但在SCM中研究不多。由此提出假设：脓毒症早期ALCAT1水平上调、CL病态重构引发SCM；后期病态CL转位促进内质网应激-线粒体自噬、清除受损线粒体而逆转SCM。本研究拟从细胞、离体、在体三个水平，首先研究脂多糖对心肌ALCAT1水平和CL重构的影响，以及这种影响与脓毒症线粒体结构/功能障碍、心肌重构的关系；进而探究病态CL转位及其对线粒体自噬、心肌结构/功能的影响。本题从线粒体CL重构角度探讨SCM早期心肌重构和存活者后期逆重构的发生机制，为完善脓毒症心肌病的诊疗策略提供新思路。

脓毒症心肌病（SCM）是造成脓毒症患者死亡和存活者再入院的主要原因，SCM可逆性心室扩张的发生机制仍不清楚。本题围绕心磷脂（CL）病态重构与线粒体自噬/细胞凋亡平衡，从线粒体、细胞及在体3个水平，研究SCM特征性心肌损伤的时程变化以及SCM心室重构/逆重构的分子机制，结果发现：①SCM早期出现一过性自噬增多，有抗凋亡作用，而后期自噬显著减少，凋亡/坏死增多，心肌结构和功能受损，其发生机制可能与AMPK/PGC1α通路有关；②SCM特征性的心室扩张与CL病态重构有关，包括L4-CL含量和CL总量显著减少及CL组成改变，而且病态CL更易被线粒体CytC氧化，而被同时高表达的线粒体翻转酶（PLSCR3）从线粒体内膜外翻至外膜，进而诱导细胞凋亡；③二十二碳六烯酸预处理可改善CL病态重构而减轻SCM相关的心肌损伤和重塑，其保护机制与p-Drp1（ser616）蛋白去磷酸化抑制线粒体分裂、降低氧化应激有关；④G蛋白偶联雌激素受体（GPER）激动剂G1可改善线粒体分裂-融合平衡、促线粒体自噬而改善心肌重塑对SCM有保护作用。本题聚焦线粒体，从CL重构角度探索了外源性补充长碳链脂酰基CL、激动GPER两条途径促线粒体自噬、改善CL重构，为降低SCM病死率、改善存活者的长期预后提供新的干预靶点。