E. Coli LPS-induced calcium signaling regulates the expression of hypoxia-inducible factor 1α in periodontal ligament fibroblasts in a non-hypoxia-dependent manner
Copyright © 2023 Elsevier B.V. All rights reserved..
Periodontitis, an inflammatory disease, can cause significant damage to the oral tissues which support the teeth. During the early development of periodontitis, periodontal ligament fibroblasts (PDLFs) undergo metabolic reprogramming regulated by hypoxia-inducible factor 1α (HIF-1α), which is strongly linked to the progression of inflammation. However, the precise mechanisms by which PDLFs regulate HIF-1α and its associated metabolic reprogramming during early inflammation remain unclear. This study illustrated that brief and low-dose exposure to Escherichia coli (E. coli) lipopolysaccharide (LPS) can serve as a non-hypoxic stimulus, effectively replicating early periodontal inflammatory reactions. This is evidenced by the upregulation of HIF-1α expression and the activation of HIF-1α-mediated crucial glycolytic enzymes, namely lactate dehydrogenase a, pyruvate kinase, and hexokinase 2, concomitant with an augmentation in the inflammatory response within PDLFs. We observed that the effects mentioned and their impact on macrophage polarization were notably attenuated when intracellular and extracellular stores of Ca2+ were depleted using BAPTA-AM and Ca2+-free medium, respectively. Mechanistically, our findings demonstrated that the transcriptional process of HIF-1α is regulated by Ca2+ during E. coli LPS stimulation, mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, we observed that the stabilization of intracellular HIF-1α proteins occurs via the endothelin (ET)-1-endothelin A receptor pathway, independent of hypoxia. Taken together, our research outcomes underscore the pivotal involvement of Ca2+ in the onset of early periodontitis by modulating HIF-1α and glycolysis, thereby presenting novel avenues for early therapeutic interventions.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:128 |
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| Enthalten in: |
International immunopharmacology - 128(2024) vom: 15. Feb., Seite 111418 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Xia [VerfasserIn] |
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| Links: |
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| Themen: |
Calcium signaling |
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| Anmerkungen: |
Date Completed 08.02.2024 Date Revised 08.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.intimp.2023.111418 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Periodontitis, an inflammatory disease, can cause significant damage to the oral tissues which support the teeth. During the early development of periodontitis, periodontal ligament fibroblasts (PDLFs) undergo metabolic reprogramming regulated by hypoxia-inducible factor 1α (HIF-1α), which is strongly linked to the progression of inflammation. However, the precise mechanisms by which PDLFs regulate HIF-1α and its associated metabolic reprogramming during early inflammation remain unclear. This study illustrated that brief and low-dose exposure to Escherichia coli (E. coli) lipopolysaccharide (LPS) can serve as a non-hypoxic stimulus, effectively replicating early periodontal inflammatory reactions. This is evidenced by the upregulation of HIF-1α expression and the activation of HIF-1α-mediated crucial glycolytic enzymes, namely lactate dehydrogenase a, pyruvate kinase, and hexokinase 2, concomitant with an augmentation in the inflammatory response within PDLFs. We observed that the effects mentioned and their impact on macrophage polarization were notably attenuated when intracellular and extracellular stores of Ca2+ were depleted using BAPTA-AM and Ca2+-free medium, respectively. Mechanistically, our findings demonstrated that the transcriptional process of HIF-1α is regulated by Ca2+ during E. coli LPS stimulation, mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, we observed that the stabilization of intracellular HIF-1α proteins occurs via the endothelin (ET)-1-endothelin A receptor pathway, independent of hypoxia. Taken together, our research outcomes underscore the pivotal involvement of Ca2+ in the onset of early periodontitis by modulating HIF-1α and glycolysis, thereby presenting novel avenues for early therapeutic interventions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Calcium signaling | |
| 650 | 4 | |a Glycolysis | |
| 650 | 4 | |a Hypoxia-inducible factor 1α | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Periodontal ligament | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Hypoxia-Inducible Factor 1, alpha Subunit |2 NLM | |
| 700 | 1 | |a Cai, Xuepei |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jiayu |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yifan |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Zhihao |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Weiyin |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, XiaoHua |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chufeng |e verfasserin |4 aut | |
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