Department of Critical Care Medicine, Geriatric ICU, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China.
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China.
Biochim Biophys Acta Mol Basis Dis. 2022 Dec 1;1868(12):166497. doi: 10.1016/j.bbadis.2022.166497. Epub 2022 Jul 20.
Sepsis-induced cardiomyopathy (SICM) has a poor prognosis, with no effective therapeutic strategy currently. This study aimed to explore the mechanism underlying SICM and investigate the protective role of the hydrogen sulfide (HS) donor GYY4137. This study included patients with SICM and animal models of SICM with wild-type and Nlrp3 mice, which were treated with or without GYY4137. Echocardiography, ELISA, TUNEL staining, and immunofluorescence were used to investigate phenotypic alterations. Serum levels of HS and cytokines were measured. Inflammatory cell infiltration in the myocardial tissue was identified using immunohistochemistry and immunofluorescence. RNA expression profiles were identified using RNA sequencing. The protective mechanism of GYY4137 was further validated in the crosstalk between macrophages and cardiomyocytes using immunoblotting, real-time polymerase chain reaction (RT-PCR), and immunofluorescence when conditional medium of macrophages boosted by LPS were co-cultured with cardiomyocytes. Patients and animal models of SICM presented with lower serum HS levels and heart dysfunction. GYY4137 reduced macrophage infiltration in septic heart tissue. GO analysis suggested that GYY4137 was involved in the inflammatory process. GYY4137 inhibited NLRP3 inflammasome activity in macrophages, reduced the secretion of inflammatory factors, and decreased the production of reactive oxygen species (ROS) in cardiomyocytes, thus exerting protective effects against SICM. We further found that the protective effects of GYY4137 were absent in Nlrp3-knockout models. GYY4137 ameliorates myocardial injury in SICM via the NLRP3 pathway by inhibiting the inflammatory response and reducing the production of myocardial ROS.
脓毒症性心肌病 (SICM) 预后较差，目前尚无有效的治疗策略。本研究旨在探讨 SICM 的发病机制，并研究硫化氢 (HS) 供体 GYY4137 的保护作用。本研究纳入了 SICM 患者和 SICM 动物模型（野生型和 Nlrp3 小鼠），并给予或不给予 GYY4137 治疗。使用超声心动图、ELISA、TUNEL 染色和免疫荧光来研究表型改变。测量血清 HS 和细胞因子水平。使用免疫组化和免疫荧光来鉴定心肌组织中的炎症细胞浸润。使用 RNA 测序来鉴定 RNA 表达谱。使用免疫印迹、实时聚合酶链反应 (RT-PCR) 和免疫荧光进一步验证 GYY4137 在巨噬细胞和心肌细胞之间的相互作用中的保护机制，当用 LPS 刺激的巨噬细胞的条件培养基与心肌细胞共培养时。SICM 患者和动物模型的血清 HS 水平较低，心脏功能受损。GYY4137 减少了脓毒症心脏组织中的巨噬细胞浸润。GO 分析表明，GYY4137 参与了炎症过程。GYY4137 抑制了巨噬细胞中 NLRP3 炎性小体的活性，减少了炎症因子的分泌，并减少了心肌细胞中活性氧 (ROS) 的产生，从而对 SICM 发挥保护作用。我们进一步发现，在 Nlrp3 基因敲除模型中，GYY4137 的保护作用消失。GYY4137 通过抑制炎症反应和减少心肌 ROS 的产生，通过 NLRP3 途径改善 SICM 中的心肌损伤。
