GYY4137 ameliorates sepsis-induced cardiomyopathy via inhibiting NLRP3 Inflammasome activity and reduction of oxidative stress in the myocardium

BACKGROUND: Sepsis-induced cardiomyopathy often leads to bad prognosis of patients, and even death. However, there is no effective therapeutic strategies for sepsis-caused cardiomyopathy. GYY4137 has positive therapeutic effects in many diseases. The aim of this study was to explore the mechanism underlying the sepsis-induced cardiomyopathy and investigate the protective role of the hydrogen sulfide (H 2 S) donor GYY4137 in sepsis-induced cardiomyopathy. METHODS: Recruitment of patients with clinical sepsis and measurement of serum H2S concentrations. GYY4137 was administrated in mouse model of sepsis-induced cardiomyopathy (SICM) was generated by LPS and cecum ligation and puncture (CLP), and then plasma levels of hydrogen sulfide and cytokines were measured, and inflammatory cell infiltration in myocardial tissue was determined by immunohistochemistry and immunofluorescence staining. RNA sequencing assay was performed to monitor the RNA expression profile. Cardiomyocytes medium was co-cultured with Macrophage, and the protective mechanism of GYY4137 was confirmed by WB, RT-PCR and immunofluorescence experiments. Establishment of SICM model using Nlrp3 -/- mice to validate the role of GYY4137. RESULTS: Compared to non-septic patients, septic patients had lower serum hydrogen sulfide concentrations and a negative correlation between hydrogen sulfide concentrations and NT-pro BNP. H 2 S levels were reduced in the serum of sepsis-molded mice, GYY4137 reduced macrophage infiltration in the sepsis model. GYY4137 reduces inflammatory cell infiltration in septic myocardial tissue. GO analysis suggested that GYY4137 involved in inflammatory regulation. GYY4137 can inhibit NLRP3 inflammasome activity in macrophages and reduce the secretion of inflammatory factors, while GYY4137 can reduce the production of reactive oxygen species in cardiomyocytes, thus exerting a protective effect on the myocardium. The protective effect of GYY4137 was disappeared after Nlrp3 knockout. CONCLUSION: GYY4137 can reduce myocardial injury in sepsis by inhibiting the inflammatory response and reducing the production of myocardial reactive oxygen species via NLRP3 pathway. It can provide new therapeutic ideas for clinical practice.