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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3
Xueyuan Long1, Yanpeng Yang1, Ke Zhou1
1Department of Cardiovascular Medicine, Chongqing University Central Hospital, Chongqing, 400014, China.
Insights
Sepsis causes heart dysfunction and apoptosis via the YAP1/Serpine1/caspase-3 pathway. A Serpine1 inhibitor reversed these effects in mice, highlighting a potential therapeutic target for sepsis-induced cardiac injury.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Sepsis Pathophysiology
Background:
- Sepsis significantly increases mortality due to myocardial injury and dysfunction.
- Cardiomyocyte apoptosis is implicated in septic myocardial injury, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of sepsis-induced myocardial injury.
- To identify key genes and pathways involved in sepsis-induced cardiac dysfunction.
- To investigate the therapeutic potential of targeting the identified pathway.
Main Methods:
- Bioinformatic analysis of gene expression in septic mouse hearts.
- In vivo sepsis model (cecal ligation and puncture) with Serpine1 inhibitor treatment.
- In vitro studies using LPS-exposed mouse cardiomyocytes to validate molecular interactions.
Main Results:
- Decreased Serpine1 expression and altered HIPPO signaling pathway in septic hearts.
- Sepsis induced cardiac dysfunction, reduced survival, and increased Serpine1 and Cleaved Caspase-3.
- Serpine1 inhibition reversed sepsis-induced cardiac dysfunction and apoptosis in vivo and in vitro.
- YAP1 and Serpine1 silencing modulated caspase-3 expression, suggesting a regulatory role.
Conclusions:
- Sepsis induces cardiomyocyte apoptosis and cardiac dysfunction through the YAP1/Serpine1/caspase-3 pathway.
- Targeting Serpine1 offers a potential therapeutic strategy for sepsis-induced cardiac injury.
Background:
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.
Methods:
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.
Results:
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. In vivo, 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. In vitro, 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.
Conclusion:
Sepsis induced mouse cardiomyocytes apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.
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