Geniposide protects against sepsis-induced myocardial dysfunction through AMPKα-dependent pathway.

Uncontrolled inflammatory response and subsequent cardiomyocytes loss (apoptosis and pyroptosis) were closely involved in sepsis-induced myocardial dysfunction. Our previous study found that geniposide (GE) could protect against obesity-induced inflammation in murine hearts. However, the effect of GE on sepsis-related cardiac dysfunction is still unknown. Mice were exposed to lipopolysaccharide (LPS) to generate sepsis-induced myocardial dysfunction. And 50 mg/kg GE was used to treat mice for consecutive 7 days. Our results showed that GE treatment significantly improved survival rate and cardiac function, and suppressed myocardial inflammatory response, as well as myocardial loss in LPS-treated mice. These effects of GE were largely abolished in NOD-like receptor protein 3 (NLRP3)-deficient mice. Further detection revealed that the inhibition of NLRP3 inflammasome activation was dependent on the reduction of p47phox by GE. GE treatment restored the phosphorylation and activity of AMP-activated protein kinase α (AMPKα) in the hearts of sepsis mice, and knockout of AMPKα abolished the protection of GE against reactive oxygen species (ROS) accumulation, NLRP3 inflammasome activation and cardiomyocytes loss in sepsis mice. In conclusion, our findings found that GE activated AMPKα to suppress myocardial ROS accumulation, thus blocking NLRP3 inflammasome-mediated cardiomyocyte apoptosis and pyroptosis and improving cardiac function in mice with sepsis.