Background: Mounting studies have illustrated an important role of HOTAIR in cancer progress, but few studies have reported its function in cardiac disease, including cardiac-associated sepsis. This study aimed to investigate the function of HOTAIR in sepsis, involving its association with the level of tumor necrosis factor-alpha (TNF-alpha), an important inducer of myocardial dysfunction during LPS-induced sepsis. Methods: Sepsis mice model was established by LPS administration, and myocardial dysfunction was evaluated with hemodynamic parameters. HOTAIR expression in isolated cardiomyocytes and TNF-alpha production in the circulation were detected, as well as the protein levels of phosphorylated p65. HL-1 cells were subjected to LPS treatment in vitro for functional studies, including luciferase report assays for NF-kappa B activity. Results: HOTAIR expression was significantly upregulated in cardiomyocytes from sepsis mice, in line with increased TNF-alpha production and p65 phosphorylation, while similar results were also observed in LPS treated HL-1 cells, which was then reversed by HOTAIR interference. Functional studies demonstrated that HOTAIR showed positive regulation on p65 phosphorylation and NF-kappa B activation, while HOTAIR-induced TNF-alpha production was repressed by NF-kappa B inhibitor. Further in vivo studies confirmed that HOTAIR silence can improve cardiac function of sepsis mice, and markedly decreased TNF-alpha production in the circulation. Conclusion: HOTAIR upregulation in cardiomyocytes of LPS-induced sepsis mice promoted TNF-alpha production in the circulation by activating NF-kappa B, involving the phosphorylation of NF-kappa B p65 subunit Moreover, HOTAIR silence preserved cardiac function of sepsis mice during LPS-induced sepsis. (C) 2016 Elsevier Inc. All rights reserved.