脓毒症合并心功能障碍导致死亡率显著上升。肾素-血管紧张素系统（RAS）在脓毒症性心功能障碍（SIMD）中扮演重要角色。血管紧张素原（AGT）作为RAS系统唯一底物，它对SIMD的调控作用不明。我们前期工作显示：脓毒症可促进小鼠肝脏，心脏组织高表达AGT，但仅敲除肝脏来源AGT可抑制SIMD，目前肝脏来源AGT调控SIMD的具体方式及机制仍不清楚。基于此，本项目拟采用多种转基因动物模型及分子生物学手段阐明以下科学假说：脓毒症可促进肝脏分泌AGT，肝脏来源的AGT通过LRP1依赖的内吞作用进入心脏成纤维细胞，继而激活心脏成纤维细胞NLRP3及caspase1活性，IL1β释放增多，从而导致成纤维细胞焦亡增加，心肌细胞存活减少，心肌收缩力减弱，最终引起心功能受损。综上，本项目将揭示AGT介导的肝脏心脏相互关联是促进SIMD的关键，从而为保护脓毒症后心功能提供新的理论依据和干预靶点。

Sepsis combined with cardiac dysfunction leads to a significant increase in mortality. The renin-angiotensin system (RAS system) plays an important role in the development of sepsis induced myocardial dysfunction (SIMD). Angiotensinogen (AGT) is the only known precursor and substrate of the RAS system, and its effect on SIMD have not been addressed. Our previous work has shown that sepsis can induce high expression of AGT both in liver and heart tissue, but only liver derived AGT can promote SIMD. However, the detailed mechanisms of liver-derived AGT regulating SIMD are still unclear. Based on these, the current project is aiming to clarify the following scientific hypothesis using a variety of transgenic animal models and molecular biological approaches: sepsis can promote the secretion of AGT from the liver, and liver derived AGT enters cardiac fibroblasts via LRP1 mediated endocytosis, which in turn activates the NLRP3 dependent fibroblast pyroptosis pathway, thus promote IL1βsecretion, reduce the survival of cardiomyocytes, inhibit myocardial contractility, and ultimately leads to cardiac dysfunction. Our project will reveal the important role of AGT, an pivotal mediator of liver heart crosstalk, on SIMD, thus provide a novel theoretical basis and potential intervention target to protect heart function after sepsis.