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HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia.

Abstract

Ouabain, a steroid binding to the Na+/K+-ATPase, has several pharmacological effects. In addition to the recognized effects of blood pressure, there is more convincing evidence suggesting that ouabain is involved in immunologic functions and inflammation. Hypoxia-inducible factor 1α (HIF-1α) is a metabolic regulator which plays a considerable role in immune responses. Previous studies had shown that HIF-1α-induced glycolysis results in functional reshaping in macrophages. In this study, we investigated the role of glycolytic pathway activation in the anti-inflammatory effect of ouabain. We found that ouabain is involved in anti-inflammatory effects both in vivo and in vitro. Additionally, ouabain can inhibit LPS-induced upregulation of GLUT1 and HK2 at the transcriptional level. GM-CSF pretreatment almost completely reversed the inhibitory effect of ouabain on LPS-induced release of proinflammatory cytokines. Alterations in glycolytic pathway activation were required for the anti-inflammatory effect of ouabain. Ouabain can significantly inhibit the upregulation of HIF-1α at the protein level. Our results also revealed that the overexpression of HIF-1α can reverse the anti-inflammatory effect of ouabain. Thus, we conclude that the HIF-1α-dependent glycolytic pathway is essential for the anti-inflammatory effect of ouabain.

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  • Authors+Show Affiliations

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China. Department of Anesthesiology, Urumqi General Hospital of Lanzhou Military Command, Urumqi 830000, China.

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

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    Department of Anesthesiology, The North Hospital of Ruijin Hospital Affiliated to the Medical College of Shanghai Jiaotong University, Shanghai 201821, China.

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

    ,

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

    Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31182997

    Citation

    Shao, Chao, et al. "HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain During Endotoxemia." Oxidative Medicine and Cellular Longevity, vol. 2019, 2019, p. 7136585.
    Shao C, Lin S, Liu S, et al. HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia. Oxid Med Cell Longev. 2019;2019:7136585.
    Shao, C., Lin, S., Liu, S., Jin, P., Lu, W., Li, N., ... Bian, J. (2019). HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia. Oxidative Medicine and Cellular Longevity, 2019, p. 7136585. doi:10.1155/2019/7136585.
    Shao C, et al. HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain During Endotoxemia. Oxid Med Cell Longev. 2019;2019:7136585. PubMed PMID: 31182997.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia. AU - Shao,Chao, AU - Lin,Shengwei, AU - Liu,Sudan, AU - Jin,Peipei, AU - Lu,Wenbin, AU - Li,Na, AU - Zhang,Yan, AU - Bo,Lulong, AU - Bian,Jinjun, Y1 - 2019/04/28/ PY - 2018/10/28/received PY - 2019/03/09/revised PY - 2019/03/24/accepted PY - 2019/6/12/entrez PY - 2019/6/12/pubmed PY - 2019/6/12/medline SP - 7136585 EP - 7136585 JF - Oxidative medicine and cellular longevity JO - Oxid Med Cell Longev VL - 2019 N2 - Ouabain, a steroid binding to the Na+/K+-ATPase, has several pharmacological effects. In addition to the recognized effects of blood pressure, there is more convincing evidence suggesting that ouabain is involved in immunologic functions and inflammation. Hypoxia-inducible factor 1α (HIF-1α) is a metabolic regulator which plays a considerable role in immune responses. Previous studies had shown that HIF-1α-induced glycolysis results in functional reshaping in macrophages. In this study, we investigated the role of glycolytic pathway activation in the anti-inflammatory effect of ouabain. We found that ouabain is involved in anti-inflammatory effects both in vivo and in vitro. Additionally, ouabain can inhibit LPS-induced upregulation of GLUT1 and HK2 at the transcriptional level. GM-CSF pretreatment almost completely reversed the inhibitory effect of ouabain on LPS-induced release of proinflammatory cytokines. Alterations in glycolytic pathway activation were required for the anti-inflammatory effect of ouabain. Ouabain can significantly inhibit the upregulation of HIF-1α at the protein level. Our results also revealed that the overexpression of HIF-1α can reverse the anti-inflammatory effect of ouabain. Thus, we conclude that the HIF-1α-dependent glycolytic pathway is essential for the anti-inflammatory effect of ouabain. SN - 1942-0994 UR - https://www.unboundmedicine.com/medline/citation/31182997/HIF1α-Induced_Glycolysis_in_Macrophage_Is_Essential_for_the_Protective_Effect_of_Ouabain_during_Endotoxemia L2 - https://dx.doi.org/10.1155/2019/7136585 DB - PRIME DP - Unbound Medicine ER -