Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
We investigated the role of the interaction between the Notch and Toll-like receptor 4 (TLR4) pathways in septic myocardial injury. The sepsis model was induced in rats with lipopolysaccharide (LPS). Rats were divided into control, LPS, LPS + TAK242 ((6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cycl...
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| Format: | Article |
| Language: | English |
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De Gruyter
2022-07-01
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| Series: | Open Life Sciences |
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| Online Access: | https://doi.org/10.1515/biol-2022-0076 |
| _version_ | 1811203783372308480 |
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| author | Liu Ziyang Li Wenli Cao Yang Zhang Xiaoxia Yang Kai Yin Fukang Yang Meng Peng Peng |
| author_facet | Liu Ziyang Li Wenli Cao Yang Zhang Xiaoxia Yang Kai Yin Fukang Yang Meng Peng Peng |
| author_sort | Liu Ziyang |
| collection | DOAJ |
| description | We investigated the role of the interaction between the Notch and Toll-like receptor 4 (TLR4) pathways in septic myocardial injury. The sepsis model was induced in rats with lipopolysaccharide (LPS). Rats were divided into control, LPS, LPS + TAK242 ((6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate) and LPS + DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycinetbutylester) groups. Heart function was evaluated with a Cardiac Doppler ultrasound. Myocardial morphological changes were detected by hematoxylin-eosin staining (H&E). Apoptosis was assessed by a TUNEL assay. The mRNA and protein levels were detected with real-time PCR, Western blot, and immunohistochemistry analysis. We found that heart function in the LPS + TAK242 group was significantly improved, but not in the LPS + DAPT group. 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. 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. 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. Conclusively, the interaction between TLR4 and Notch signaling pathways enhances the inflammatory response in the septic heart by activating NF-κB. 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. |
| first_indexed | 2024-04-12T03:01:03Z |
| format | Article |
| id | doaj.art-a61c415874a349cb812f46b06bc6318f |
| institution | Directory Open Access Journal |
| issn | 2391-5412 |
| language | English |
| last_indexed | 2024-04-12T03:01:03Z |
| publishDate | 2022-07-01 |
| publisher | De Gruyter |
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| series | Open Life Sciences |
| spelling | doaj.art-a61c415874a349cb812f46b06bc6318f2022-12-22T03:50:40ZengDe GruyterOpen Life Sciences2391-54122022-07-0117174475510.1515/biol-2022-0076Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heartLiu Ziyang0Li Wenli1Cao Yang2Zhang Xiaoxia3Yang Kai4Yin Fukang5Yang Meng6Peng Peng7Intensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaEmergency Department of Internal Medicine, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaIntensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaIntensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaIntensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaIntensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaIntensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaIntensive Care Unit, Emergency Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, ChinaWe investigated the role of the interaction between the Notch and Toll-like receptor 4 (TLR4) pathways in septic myocardial injury. The sepsis model was induced in rats with lipopolysaccharide (LPS). Rats were divided into control, LPS, LPS + TAK242 ((6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate) and LPS + DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycinetbutylester) groups. Heart function was evaluated with a Cardiac Doppler ultrasound. Myocardial morphological changes were detected by hematoxylin-eosin staining (H&E). Apoptosis was assessed by a TUNEL assay. The mRNA and protein levels were detected with real-time PCR, Western blot, and immunohistochemistry analysis. We found that heart function in the LPS + TAK242 group was significantly improved, but not in the LPS + DAPT group. 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. 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. 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. Conclusively, the interaction between TLR4 and Notch signaling pathways enhances the inflammatory response in the septic heart by activating NF-κB. 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.https://doi.org/10.1515/biol-2022-0076sepsismyocardial injurytlr4notchnf-κb |
| spellingShingle | Liu Ziyang Li Wenli Cao Yang Zhang Xiaoxia Yang Kai Yin Fukang Yang Meng Peng Peng Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart Open Life Sciences sepsis myocardial injury tlr4 notch nf-κb |
| title | Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart |
| title_full | Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart |
| title_fullStr | Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart |
| title_full_unstemmed | Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart |
| title_short | Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart |
| title_sort | effects of the interaction of notch and tlr4 pathways on inflammation and heart function in septic heart |
| topic | sepsis myocardial injury tlr4 notch nf-κb |
| url | https://doi.org/10.1515/biol-2022-0076 |
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