Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Alleviates Sepsis-Induced Cardiomyopathy by Inhibiting Pyroptosis

Background: Sepsis-induced cardiomyopathy (SIC) is a common complication of sepsis accompanied by high prevalence and mortality in sepsis patients. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor, and it exerts critical functions in various diseases, including heart diseases, while its effect on SIC remains elusive. Hence, we aimed to investigate the action of MANF on SIC.Methods: This study was under the guidance of Gongli Hospital, Shanghai, China from January 2021 to De-cember 2021. H9c2 cells and mice were induced by LPS to establish SIC in vitro and in vivo models. qRT-PCR and Western blot were used to determine gene and protein expressions. The levels of MANF, Interleukin-1 beta (IL-1 beta), Interleukin 18 (IL-18), creatine kinase-MB (CK-MB), and cardiac troponin I (cTn I) were detected us-ing ELISA assay. Cell pyroptosis determination was performed by flow cytometry. The DCFDA assay kit was used to determine ROS production. Results: In SIC in vitro model, LPS induced cell pyroptosis (P<0.001) and ROS accumulation (P<0.001). Be-sides, MANF was decreased in LPS-induced H9c2 cells (P<0.001) and SIC patients (P<0.001). In addition, overexpression of MANF ameliorated SIC-induced injury in H9C2 cells (P<0.001). Furthermore, inhibition of NLRP3 rescued the function of MANF on SIC-induced injury in H9C2 cells (P<0.001). Moreover, enforced MANF suppressed the SIC-induced injury in vivo model (P<0.001). Conclusion: MANF was down-regulated in SIC. Overexpressed MANF ameliorated the SIC injury by inhibit-ing NLRP3-mediated pyroptosis.