PLCE1 enhances mitochondrial dysfunction to promote GSDME-mediated pyroptosis in doxorubicin-induced cardiotoxicity

Abstract

BackgroundThe therapeutic value and long-term application of doxorubicin (DOX) were hampered by its severe irreversible cardiotoxicity. Phospholipase C epsilon 1 (PLCE 1) was reported as a new member of the phospholipase C (PLC) family which controls the level of phosphoinositides in cells. Pyroptosis is a newly discovered inflammatory type of regulated cell death. Recent studies have consolidated that chemotherapeutic drugs lead to pyroptosis. Additionally, the phosphoinositide signaling system has remarkable effects on the execution of cell death. We aim to investigate the role of PLCE1 and the mechanism of pyroptosis from the context of DOX-induced cardiotoxicity. MethodsIn the current study, in vitro and in vivo experiments were performed to dissect the underlying mechanism of cardiomyocyte pyroptosis during DOX-induced cardiac injury. The molecular mechanism of PLCE1 was identified by the human cardiomyocyte AC16 cell line and C57BL/6 mouse model. ResultsThe results here indicated that PLCE1 high expressed and pyroptotic cell death presented in cardiomyocytes after DOX application, which was negatively correlated to heart function. DOX-induced cell model disclosed pyroptosis mediated by Gasdermin E (GSDME) protein and involved in mitochondrial damage. Conversely, the deletion of PLCE1 ameliorated mitochondrial dysfunction by suppressing ROS accumulation and reversing mitochondrial membrane potential, and then increased cell viability effectively. More importantly, the in vivo experiment demonstrated that inhibition of PLCE1 reduced pyroptotic cell death and improved heart effect. ConclusionsWe discovered firstly that PLCE1 inhibition protected cardiomyocytes from DOX-induced pyroptotic injury and promoted cardiac function. This information offers a theoretical basis for promising therapy.