Abstract：
Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.
摘要：
心功能不全,内毒素血症的早期并发症，是重症监护病房死亡的主要原因.目前尚无针对这种心脏功能障碍的特定疗法。这里,我们表明，在内毒素血症期间，N末端gasderminD（GSDMD-N）通过与复合物II产生的活性氧（ROS）氧化的心磷脂直接相互作用，从而引发线粒体凋亡孔和心功能障碍。胱天蛋白酶-4/11启动GSDMD-N孔,其随后通过NLRP3炎症的上调和活化通过进一步产生ROS而被扩增。GSDMD-N孔在BAX和VDAC1凋亡孔之前形成，并进一步掺入线粒体膜内的BAX和VDAC1寡聚体中以加剧凋亡过程。我们的发现确定氧化心磷脂是内毒素诱导的心肌功能障碍（EIMD）过程中心肌细胞线粒体中GSDMD-N的确定目标，心磷脂氧化的调节可能是疾病早期预防EIMD的治疗靶点。
