Targeting Hypoxia-Inducible Factor-1α/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis
| Autor: | Jung Whan Kim, Vladimir Shulaev, Meng Hsiung Hsieh, Norihiko Takeda, Shanta Dhar, Pankaj K. Singh, Jung-Mo Ahn, Inkyu Lee, Heather N. Hayenga, Hyunsung Choi, David B. Shackelford, Justin Goodwin, Michael L. Neugent |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine medicine.medical_specialty Pyruvate dehydrogenase kinase Pulmonary Fibrosis Clinical Biochemistry Biology Protein Serine-Threonine Kinases Cell Line 03 medical and health sciences Bleomycin Mice 0302 clinical medicine Internal medicine Pulmonary fibrosis medicine Animals Humans Glycolysis RNA Small Interfering Myofibroblasts Molecular Biology Lung Original Research Mice Knockout Dichloroacetic Acid Pyruvate Dehydrogenase Acetyl-Transferring Kinase Cell Biology Hypoxia (medical) medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia 030104 developmental biology Endocrinology HIF1A Hypoxia-inducible factors 030220 oncology & carcinogenesis Knockout mouse Cancer research RNA Interference medicine.symptom Myofibroblast |
| Popis: | Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-β-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis. |
| Databáze: | OpenAIRE |
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