HIF1α-Induced Glycolysis in Macrophage Is Essential for the Protective Effect of Ouabain during Endotoxemia. (28th April 2019) - Shao, Chao
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 1 α (HIF-1 α ) is a metabolic regulator which plays a considerable role in immune responses. Previous studies had shown that HIF-1 α -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-1 α at the protein level. Our results also revealed that the overexpression of HIF-1 α can reverse the anti-inflammatory effect of ouabain. Thus, we conclude that the HIF-1 α -dependent glycolytic pathway is essential for the anti-inflammatory effect of ouabain.