Cardiac Resolvin D2 ameliorates sepsis-induced cardiomyopathy via inhibiting Caspase-11/GSDMD dependent pyroptosis

Background: Sepsis-induced cardiomyopathy (SICM) is common complication in septic patients with a high mortality and is characterized by an abnormal inflammation response, which was precisely regulated by endogenous specialized pro-resolving mediators (SPMs). However, the metabolic changes of cardiac SPMs during SICM and the roles of SPMs subset in the development of SICM remain unknown.

Methods: In this work, the SPMs concentration was assessed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) of SICM mice and SICM patients. The cardiac function was measured by echocardiography after the treatment of a SPMs subset, termed Resolvin D2 (RvD2). Caspase-11^-/-, GSDMD^-/- and double deficient (Caspase-11^-/-GSDMD^-/-) mice were used to clarify the mechanisms of RvD2 in SICM.

Results: We found that endogenous cardiac SPMs were disorders and RvD2 was decreased significantly and correlated with left ventricular ejection fraction (LVEF) and β-BNP, cTnT in Lipopolysaccharide/Cecum ligation and puncture (CLP) induced SICM models. Treatment with RvD2 attenuated lethality, cardiac dysfunction and cardiomyocytes death during SICM. Mechanistically, RvD2 alleviated SICM via inhibiting Caspase-11/GSDMD-mediated cardiomyocytes pyroptosis. Finally, the plasma levels of RvD2 were also decreased and significantly correlated with IL-1β, β-BNP, cTnT and LVEF in patients with SICM. Of note, plasma RvD2 level is indicator of SICM patients from healthy controls or sepsis patients.

Conclusion: These findings suggest that decreased cardiac RvD2 may involve in the pathogenesis of SICM. In addition, treatment with RvD2 represents a novel therapeutic strategy for SICM by inhibiting cardiomyocytes pyroptosis.