Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart

Tomohiro Matsuhashi, Takako Hishiki, Heping Zhou, Tomohiko Ono, Ruri Kaneda, Tatsuya Iso, Aiko Yamaguchi, Jin Endo, Yoshinori Katsumata, Atsushi Anzai, Tsunehisa Yamamoto, Kosuke Shirakawa, Xiaoxiang Yan, Ken Shinmura, Makoto Suematsu, Keiichi Fukuda, Motoaki Sano

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. <sup>13</sup>C<inf>6</inf>-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.

Original languageEnglish
Pages (from-to)116-124
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume82
DOIs
Publication statusPublished - 2015 May 1

Fingerprint

Pyruvic Acid
Epigenomics
Oxidoreductases
Histones
Citric Acid Cycle
Acetylation
Acetyl Coenzyme A
Therapeutic Uses
Pressure
Glucose
Gene Ontology
Ventricular Remodeling
Cardiac Myocytes
Genes
Oral Administration
Mitochondria
Up-Regulation
Carbon
Heart Failure
Adenosine Triphosphate

Keywords

  • Acetylation
  • Ketone
  • Metabolic modulation therapy
  • Metabolomics

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart. / Matsuhashi, Tomohiro; Hishiki, Takako; Zhou, Heping; Ono, Tomohiko; Kaneda, Ruri; Iso, Tatsuya; Yamaguchi, Aiko; Endo, Jin; Katsumata, Yoshinori; Anzai, Atsushi; Yamamoto, Tsunehisa; Shirakawa, Kosuke; Yan, Xiaoxiang; Shinmura, Ken; Suematsu, Makoto; Fukuda, Keiichi; Sano, Motoaki.

In: Journal of Molecular and Cellular Cardiology, Vol. 82, 01.05.2015, p. 116-124.

Research output: Contribution to journalArticle

Matsuhashi, T, Hishiki, T, Zhou, H, Ono, T, Kaneda, R, Iso, T, Yamaguchi, A, Endo, J, Katsumata, Y, Anzai, A, Yamamoto, T, Shirakawa, K, Yan, X, Shinmura, K, Suematsu, M, Fukuda, K & Sano, M 2015, 'Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart', Journal of Molecular and Cellular Cardiology, vol. 82, pp. 116-124. https://doi.org/10.1016/j.yjmcc.2015.02.021
Matsuhashi, Tomohiro ; Hishiki, Takako ; Zhou, Heping ; Ono, Tomohiko ; Kaneda, Ruri ; Iso, Tatsuya ; Yamaguchi, Aiko ; Endo, Jin ; Katsumata, Yoshinori ; Anzai, Atsushi ; Yamamoto, Tsunehisa ; Shirakawa, Kosuke ; Yan, Xiaoxiang ; Shinmura, Ken ; Suematsu, Makoto ; Fukuda, Keiichi ; Sano, Motoaki. / Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 82. pp. 116-124.
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AU - Kaneda, Ruri

AU - Iso, Tatsuya

AU - Yamaguchi, Aiko

AU - Endo, Jin

AU - Katsumata, Yoshinori

AU - Anzai, Atsushi

AU - Yamamoto, Tsunehisa

AU - Shirakawa, Kosuke

AU - Yan, Xiaoxiang

AU - Shinmura, Ken

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AU - Fukuda, Keiichi

AU - Sano, Motoaki

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N2 - Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. 13C6-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.

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