Targeting hypoxia-inducible factor-1a/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis

Justin Goodwin, Hyunsung Choi, Meng Hsiung Hsieh, Michael L. Neugent, Jung Mo Ahn, Heather N. Hayenga, Pankaj Singh, David B. Shackelford, In Kyu Lee, Vladimir Shulaev, Shanta Dhar, Norihiko Takeda, Jung Whan Kim

Research output: Contribution to journalEditorial

10 Citations (Scopus)

Abstract

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-b-induced myofibroblast differentiation through HIF-1a, whereas overexpression of the critical HIF-1a-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1a. Inhibition of the HIF-1a/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1a/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.

Original languageEnglish (US)
Pages (from-to)216-231
Number of pages16
JournalAmerican journal of respiratory cell and molecular biology
Volume58
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Myofibroblasts
Pulmonary Fibrosis
Bleomycin
Metabolism
Transforming Growth Factors
Fibroblasts
Pharmacology
Chemical activation
Switches
Glycolysis
Knockout Mice
pyruvate dehydrogenase (acetyl-transferring) kinase
Hypoxia
Lung

Keywords

  • Dichloroacetate
  • Fibroblasts
  • Hypoxia inducible factor-1a
  • Pulmonary fibrosis
  • Pyruvate dehydrogenase kinase1

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Targeting hypoxia-inducible factor-1a/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis. / Goodwin, Justin; Choi, Hyunsung; Hsieh, Meng Hsiung; Neugent, Michael L.; Ahn, Jung Mo; Hayenga, Heather N.; Singh, Pankaj; Shackelford, David B.; Lee, In Kyu; Shulaev, Vladimir; Dhar, Shanta; Takeda, Norihiko; Kim, Jung Whan.

In: American journal of respiratory cell and molecular biology, Vol. 58, No. 2, 01.02.2018, p. 216-231.

Research output: Contribution to journalEditorial

Goodwin, J, Choi, H, Hsieh, MH, Neugent, ML, Ahn, JM, Hayenga, HN, Singh, P, Shackelford, DB, Lee, IK, Shulaev, V, Dhar, S, Takeda, N & Kim, JW 2018, 'Targeting hypoxia-inducible factor-1a/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis', American journal of respiratory cell and molecular biology, vol. 58, no. 2, pp. 216-231. https://doi.org/10.1165/rcmb.2016-0186OC
Goodwin, Justin ; Choi, Hyunsung ; Hsieh, Meng Hsiung ; Neugent, Michael L. ; Ahn, Jung Mo ; Hayenga, Heather N. ; Singh, Pankaj ; Shackelford, David B. ; Lee, In Kyu ; Shulaev, Vladimir ; Dhar, Shanta ; Takeda, Norihiko ; Kim, Jung Whan. / Targeting hypoxia-inducible factor-1a/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis. In: American journal of respiratory cell and molecular biology. 2018 ; Vol. 58, No. 2. pp. 216-231.
@article{edb8d73f930141bfaed73c8d1fa0ec21,
title = "Targeting hypoxia-inducible factor-1a/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis",
abstract = "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-b-induced myofibroblast differentiation through HIF-1a, whereas overexpression of the critical HIF-1a-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1a. Inhibition of the HIF-1a/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1a/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.",
keywords = "Dichloroacetate, Fibroblasts, Hypoxia inducible factor-1a, Pulmonary fibrosis, Pyruvate dehydrogenase kinase1",
author = "Justin Goodwin and Hyunsung Choi and Hsieh, {Meng Hsiung} and Neugent, {Michael L.} and Ahn, {Jung Mo} and Hayenga, {Heather N.} and Pankaj Singh and Shackelford, {David B.} and Lee, {In Kyu} and Vladimir Shulaev and Shanta Dhar and Norihiko Takeda and Kim, {Jung Whan}",
year = "2018",
month = "2",
day = "1",
doi = "10.1165/rcmb.2016-0186OC",
language = "English (US)",
volume = "58",
pages = "216--231",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "2",

}

TY - JOUR

T1 - Targeting hypoxia-inducible factor-1a/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis

AU - Goodwin, Justin

AU - Choi, Hyunsung

AU - Hsieh, Meng Hsiung

AU - Neugent, Michael L.

AU - Ahn, Jung Mo

AU - Hayenga, Heather N.

AU - Singh, Pankaj

AU - Shackelford, David B.

AU - Lee, In Kyu

AU - Shulaev, Vladimir

AU - Dhar, Shanta

AU - Takeda, Norihiko

AU - Kim, Jung Whan

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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-b-induced myofibroblast differentiation through HIF-1a, whereas overexpression of the critical HIF-1a-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1a. Inhibition of the HIF-1a/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1a/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.

AB - 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-b-induced myofibroblast differentiation through HIF-1a, whereas overexpression of the critical HIF-1a-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1a. Inhibition of the HIF-1a/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1a/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.

KW - Dichloroacetate

KW - Fibroblasts

KW - Hypoxia inducible factor-1a

KW - Pulmonary fibrosis

KW - Pyruvate dehydrogenase kinase1

UR - http://www.scopus.com/inward/record.url?scp=85043335053&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043335053&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2016-0186OC

DO - 10.1165/rcmb.2016-0186OC

M3 - Editorial

VL - 58

SP - 216

EP - 231

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 2

ER -