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PIK3CG Regulates NLRP3/GSDMD-Mediated Pyroptosis in Septic Myocardial Injury
Chenxi Lu1, Jie Liu1, Germaine Escames2
1Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an 710069, China.
Insights
Phosphoinositide 3-kinase gamma (PIK3CG) promotes pyroptosis in septic myocardial injury by activating NLRP3 inflammasomes. Inhibiting PIK3CG can reverse this damage, offering a potential therapeutic target for sepsis-induced heart problems.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis commonly causes cardiac insufficiency and high mortality.
- Pyroptosis, mediated by NLRP3/gasdermin D (GSDMD), is linked to septic myocardial injury.
- The role of PIK3CG in pyroptosis during sepsis remains unclear.
Purpose of the Study:
- To investigate the effect of PIK3CG on NLRP3/GSDMD-mediated pyroptosis in septic myocardial injury.
- To explore PIK3CG as a potential therapeutic target for sepsis-induced heart damage.
Main Methods:
- Cecal ligation and puncture (CLP) model in BALB/c mice.
- Lipopolysaccharide (LPS) stimulation in HL-1 cardiomyocytes.
- Transcriptome analysis and GEO database verification.
- PIK3CG siRNA, overexpression, and inhibitor (AS-604850) treatments.
Main Results:
- PIK3CG, NLRP3, GSDMD, IL-1β, Caspase-1, and IL-18 levels were elevated in septic myocardial injury models.
- PIK3CG siRNA treatment ameliorated these increases, while PIK3CG overexpression exacerbated them.
- The PIK3CG inhibitor AS-604850 reversed pyroptosis induced by CLP in myocardial tissue.
Conclusions:
- PIK3CG activates NLRP3 inflammasomes, promoting pyroptosis in septic myocardial injury.
- Targeting PIK3CG may offer a novel therapeutic strategy for sepsis-related cardiac dysfunction.
Abstract:
Cardiac insufficiency is a common complication of sepsis with high mortality. Inflammatory programmed cell death (pyroptosis) executed by NLRP3/gasdermin D (GSDMD) is intrinsically correlated with septic myocardial injury. However, it remains unclear whether PIK3CG, a classical target of septic myocardial injury, can affect pyroptosis by regulating NLRP3/GSDMD signaling. In this study, a series of experimental methods were used to observe the effect of PIK3CG on NLRP3/GSDMD-mediated pyroptosis in Cecal ligation and puncture (CLP)-injured BALB/c mice and lipopolysaccharide (LPS)-injured HL-1 cardiomyocytes. Transcriptome analysis of CLP-injured myocardium revealed a regulatory relationship between PIK3CG and NLRP3/GSDMD signaling, which was further verified in clinical myocardium samples from GEO database. Both in vitro and in vivo experiments showed that the protein and mRNA levels of PIK3CG, GSDMD, NLRP3, IL-1β, Caspase-1, and IL-18 were significantly increased. Importantly, PIK3CG siRNA was found to improve these changes, while PIK3CG overexpression worsened them. Notably, pyroptosis induced by CLP in the myocardium was reversed by the PIK3CG inhibitor (AS-604850). In conclusion, PIK3CG activates NLRP3 inflammasomes, thus promoting pyroptosis in septic myocardial injury.
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