Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway

Backgrounds: Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, possess cardio-protective, their effects on sepsis-induced cardiomyopathy remain unknown.Methods: C57BL/6 mice received subcutaneous injections of tirzepatide once a day for 14 days before subjected to LPS challenge for 12 h. LPS-induced cardiac dysfunction and its potential mechanisms were estimated by pathological analysis, echocardiographic measurement, electrocardiography, langendorff-perfused heart and molecular analysis. Results: Pretreatment with tirzepatide attenuates LPS-induced cardiac dysfunction. tirzepatide remarkably reduces LPS-mediated inflammatory responses by inhibiting the cardiac protein levels of TNF-a, IL-6, and IL-1B in mice. Interestingly, tirzepatide administration also improves cardiomyocytes apoptosis caused by LPS treatment. Furthermore, the protective roles of irzepatide against LPS-mediated increased inflammatory responses and decreased cardiomyocytes apoptosis are partially blunted by inhibiting TLR4/NF-kB/NLRP3 inflammation signaling. In addition, tirzepatide reduce the susceptibility ventricular arrhythmia in LPS-treated mice.Conclusion: In brief, tirzepatide attenuates LPS-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway.