MolecuLar Mechanism Of Protective Effect Of Metformin On Septic Myocarditis

Sepsis is a multiple organ dysfunction and systemic response syndrome caused by endotoxin released from bacterial infection or bacterial infection.During septic shock,the heart is one of the most vulnerable organs.Septic cardiomyopathy(SIC)is a cardiovascular disease associated with infection.Studies have shown that at least 50% of septic shock patients are clinically diagnosed as septic cardiomyopathy,which is caused by myocardial dysfunction and indicates poor prognosis of septic shock.At present,little is known about the specific mechanism of myocardial dysfunction induced by Escherichia coli and LPS,and because of its mixed factors with sepsis itself,there is little clinical effect on septic cardiomyopathy patients.In order to better study the mechanism of immune cells in the development of sepsis-induced cardiomyopathy,a large number of drugs were screened.Metformin was found to effectively inhibit myocardial injury in mice and zebrafish models of sepsis-induced cardiomyopathy.By studying the pathological changes of the heart of mice and zebrafish in septic cardiomyopathy,the types and morphological changes of cardiac myocytes,and the changes of related cytokines after the translocation of key proteins in cardiomyocytes,we preliminarily explored the protective mechanism of metformin on septic cardiomyopathy,in order to provide the follow-up for sepsis and providing new ideas for prevention and treatment of hemorrhagic cardiomyopathy.(1)Sepsis model group: 8-week-old female C57BL/6J mice were selected,and 1 m L lethal dose of bacteria was slowly injected into the abdominal cavity of the right lower abdomen of the mice.(2)Metformin preconditioning protection group(In P): 1?g/100?L of metformin wasslowly injected into the abdominal cavity of the right lower abdomen of mice,and 1 m L lethal dose of bacteria was slowly injected into the abdomen of mice at intervals of 2 hours.(3)Metformin alone group: 1?g/100?L Metformin was slowly injected into the abdominal cavity of the right lower abdomen for 2 hours;(4)Zebrafish was soaked in LPS,the other steps were the same as above.CONCLUSION: When metformin stimulates cardiac myocytes,PKC epsilon in the cytoplasm inhibits the MAPK/JNK signaling pathway by translocation to the cell membrane and binding to Caveolin-3,and protects cardiac myocytes by reducing the proportion of Bcl-2/Bax protein.At the same time,metformin stimulates cardiac myocytes in mitochondria,through the formation of complex with PKC epsilon and IRF4,and through the release of anti-inflammatory factors IL-10,TGF-beta,playing an anti-inflammatory role,thus inhibit the occurrence and development of septic cardiomyopathy.