![]() The activated TLR4 signal may directly regulate the Notch cascade through the histone modification at the target gene sites of Notch or indirectly regulate the Notch cascade by inducing the Notch receptors and ligands. There is crosstalk between the Notch and TLR4 signaling pathways. On the other hand, after the Notch receptor binds to its ligand, its transmembrane domain would be cleaved by the γ-endocrine enzyme complex to release the intracellular active form of Notch intracellular domain (NICD), which enters the nucleus to interact with target genes and induce the transcription of Notch target genes (such as the Hairy and Enhancer of Split 1 gene). Many studies have shown that the inflammatory response induced by the TLR4 pathway plays an important role in myocardial injury caused by sepsis. In sepsis, how to reduce severe myocardial damage and the occurrence of heart dysfunction have attracted much attention.Īfter activation, TLR4 can induce inflammation and the expression of nuclear factor kappa-B (NF-κB)-dependent pro-inflammatory cytokines, such as the tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). However, there is no specific effective treatment for sepsis patients therefore, sepsis has been mainly treated by controlling the infection with antibiotics and supporting the organ function. LPS is the main component of the cell wall of gram-negative bacteria and has been widely used for inducing sepsis models. It can trigger immune responses and act as an early signal of pathogenic microbial infection. Lipopolysaccharide (LPS), which is a pathogen-associated molecular pattern, is recognized by TLR4. In sepsis, the toll-like receptors (TLRs), inflammasomes, and other pattern recognition receptors would initiate the immune responses after recognizing the pathogen-associated molecular patterns derived from microorganisms. When patients with sepsis have heart dysfunction, the mortality rate may be significantly increased by 20–50%. Heart dysfunction in sepsis is associated with significantly increased mortality. Patients with sepsis may suffer from various degrees of heart dysfunction, and in severe cases, sepsis may lead to multiple organ failure. Currently, the in-hospital sepsis and septic shock mortality remains as high as 20–30%. ![]() Sepsis is defined as the life-threatening multiple organ dysfunction caused by the imbalance of the host response to infection, which has been recognized as the main cause of death in intensive care units. Blocking the TLR4 pathway with TAK242 can improve heart dysfunction and myocardial damage in sepsis, while blocking the Notch pathway with DAPT cannot effectively prevent heart dysfunction and myocardial damage in sepsis. Conclusively, the interaction between TLR4 and Notch signaling pathways enhances the inflammatory response in the septic heart by activating NF-κB. Additionally, the expression levels of tumor necrosis factor-α and Interleukin-6, the protein contents of Notch intracellular domain and Hes1, and the P65 nuclear factor kappa-B (NF-κB) to P-P65 NF-κB ratio in LPS + TAK242 group and LPS + DAPT group were significantly lower than those in LPS group. Compared with the LPS group, the inflammatory cell infiltration was reduced in the LPS + DAPT group, while the degeneration and necrosis of cardiomyocytes were not obviously improved. LPS + TAK242 had a lower level of degeneration and necrosis of cardiomyocytes and inflammatory cell infiltration, as well as lower apoptosis and caspase-3 expression than the LPS group. We found that heart function in the LPS + TAK242 group was significantly improved, but not in the LPS + DAPT group. The mRNA and protein levels were detected with real-time PCR, Western blot, and immunohistochemistry analysis. Myocardial morphological changes were detected by hematoxylin-eosin staining (H&E). Heart function was evaluated with a Cardiac Doppler ultrasound. Rats were divided into control, LPS, LPS + TAK242 ((6 R)-6-cyclohex-1-ene-1-carboxylate) and LPS + DAPT ( N- s-phenylglycinetbutylester) groups. The sepsis model was induced in rats with lipopolysaccharide (LPS). We investigated the role of the interaction between the Notch and Toll-like receptor 4 (TLR4) pathways in septic myocardial injury.
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