HIF1 α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia

Oxid Med Cell Longev. 2019 Apr 28;2019:7136585. doi: 10.1155/2019/7136585. eCollection 2019.

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.

MeSH terms

  • Animals
  • Endotoxemia / chemically induced
  • Endotoxemia / drug therapy*
  • Endotoxemia / metabolism*
  • Glycolysis / drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Hypoxia-Inducible Factor 1 / pharmacology*
  • Lipopolysaccharides / toxicity
  • Macrophages / drug effects*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Ouabain / therapeutic use*
  • Real-Time Polymerase Chain Reaction
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • Hypoxia-Inducible Factor 1
  • Lipopolysaccharides
  • Ouabain
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Sodium-Potassium-Exchanging ATPase