Long Xueyuan, Yang Yanpeng, Zhou Ke
Department of Cardiovascular Medicine, Chongqing University Central Hospital, Chongqing, 400014, China.
Open Med (Wars). 2024 Sep 17;19(1):20241018. doi: 10.1515/med-2024-1018. eCollection 2024.
Sepsis triggers myocardial injury and dysfunction, leading to a high mortality rate in patients. Cardiomyocyte apoptosis plays a positive regulatory role in septic myocardial injury and dysfunction. However, the mechanism is unclear.
Bioinformatics analysis was used to identify differentially expressed genes in septic mice heart and validate key genes and pathways. The correlation of protein-protein and protein-pathway was analyzed. Sequentially, the cecal ligament and puncture (CLP) was used to induce septic mice, followed by Serpine1 inhibitor treatment. Finally, the regulatory relationship of Yes-associated protein1 (YAP1), Serpine1, and caspase-3 was verified in LPS-exposed mouse cardiomyocytes.
Bioinformatic analysis found that Serpine1 expression is decreased in septic mice heart tissue and closely related to the HIPPO signaling pathway, while YAP1 is negatively correlated with apoptosis. , CLP induced a reduction of survival rate, cardiac dysfunction, and an increase in Serpine1 and Cleaved Caspase-3 expression, which could be reversed by a Serpine1 inhibitor. , LPS induced the mouse cardiomyocytes apoptosis, which could be reversed by Serpine1 inhibitor. Silencing YAP1 and Serpine1 reversed the LPS-induced increase in Serpine1 and Cleaved Caspase-3 expression, but silencing Serpine1 did not affect the LPS-induced YAP1 expression.
Sepsis induced mouse cardiomyocytes apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.
脓毒症引发心肌损伤和功能障碍，导致患者死亡率很高。心肌细胞凋亡在脓毒症性心肌损伤和功能障碍中起正向调节作用。然而，其机制尚不清楚。
采用生物信息学分析来鉴定脓毒症小鼠心脏中差异表达的基因，并验证关键基因和信号通路。分析蛋白质-蛋白质和蛋白质-信号通路的相关性。随后，采用盲肠结扎和穿刺（CLP）诱导脓毒症小鼠，接着进行丝氨酸蛋白酶抑制剂1（Serpine1）治疗。最后，在脂多糖（LPS）刺激的小鼠心肌细胞中验证Yes相关蛋白1（YAP1）、Serpine1和半胱天冬酶-3（caspase-3）的调控关系。
生物信息学分析发现，脓毒症小鼠心脏组织中Serpine1表达降低，且与HIPPO信号通路密切相关，而YAP1与细胞凋亡呈负相关。CLP诱导生存率降低、心脏功能障碍以及Serpine1和裂解型半胱天冬酶-3表达增加，而丝氨酸蛋白酶抑制剂1可逆转这些变化。LPS诱导小鼠心肌细胞凋亡，丝氨酸蛋白酶抑制剂1可逆转这一过程。沉默YAP1和Serpine1可逆转LPS诱导的Serpine1和裂解型半胱天冬酶-3表达增加，但沉默Serpine1并不影响LPS诱导的YAP1表达。
脓毒症通过激活YAP1/Serpine1/caspase-3信号通路诱导小鼠心肌细胞凋亡和心脏功能障碍。
