Study on the effect of inhibiting IL-6 trans-signaling pathway on cardiac function in sepsis-induced heart dysfunction mice and its mechanism

Introduction Sepsis-induced myocardial dysfunction (SIMD) is a severe complication with high mortality, and IL-6 trans-signaling has been implicated in its pathophysiology. However, the specific mechanisms and therapeutic potential of targeting this pathway remain to be fully elucidated. This study aimed to investigate the role of IL-6 trans-signaling in SIMD and to evaluate the cardioprotective effects of its specific inhibitor, sgp130Fc, both in vivo and in vitro. Methods Clinical serum samples were collected from septic patients with and without cardiac dysfunction and subsequently analyzed. A murine model of SIMD was established CLP. The selective IL-6 trans-signaling inhibitor, sgp130Fc, was administered as a therapeutic intervention. Cardiac function was evaluated using echocardiography, specifically measuring LVEF and LVFS. Histopathological analyses, including HE staining, Masson’s trichrome staining, and TUNEL assay, along with transmission electron microscopy, were conducted to assess myocardial injury, apoptosis, fibrosis, and ultrastructural alterations. In vitro, LPS-stimulated cardiomyocytes, cardiac fibroblasts, and cardiac microvascular endothelial cells were utilized to explore the protective mechanisms of sgp130Fc. Additionally, a JAK agonist was applied in rescue experiments to validate the involvement of the JAK/STAT3 signaling pathway. Results Serum concentrations of IL-6, sIL-6R, cardiac injury biomarkers (cTnI, CK-MB, NT-proBNP), as well as markers of fibrosis and endothelial dysfunction, were significantly increased in patients with sepsis, particularly in those with SIMD, whereas sgp130 levels were notably reduced. In the CLP mouse model, administration of sgp130Fc significantly enhanced survival rates and cardiac function, suppressed the production of inflammatory cytokines and injury biomarkers, decreased cardiomyocyte apoptosis, mitigated myocardial fibrosis, and preserved mitochondrial and myocardial ultrastructural integrity. In vitro studies demonstrated that sgp130Fc protected all three major cardiac cell types from LPS-induced injury by restoring cell viability, attenuating inflammatory and fibrotic responses, and enhancing functional properties, including proliferation, migration, and apoptosis regulation. Importantly, the administration of a JAK agonist effectively counteracted the protective effects of sgp130Fc in both in vivo and in vitro models. Mechanistically, sgp130Fc treatment markedly inhibited the activation of the JAK/STAT3 signaling pathway, while the JAK agonist restored pathway activity. Conclusion IL-6 trans-signaling is hyperactivated in SIMD and contributes to myocardial injury. The selective inhibitor sgp130Fc confers comprehensive cardioprotection by mitigating inflammation, apoptosis, fibrosis, and ultrastructural damage. The protective mechanism is primarily mediated through the multi-cellular inhibition of the JAK/STAT3 signaling pathway. Targeting IL-6 trans-signaling with sgp130Fc represents a promising therapeutic strategy for SIMD.