Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart.
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. (13)C6-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.
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Tomohiro
T
Matsuhashi
Department of Biochemistry, Keio University, School of Medicine, Tokyo, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo, Japan.
Takako
T
Hishiki
Department of Cardiovascular Surgery, First affiliated Hospital, Fourth Military Medical University, Xi'an, China.
Heping
H
Zhou
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Tomohiko
T
Ono
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan.
Ruri
R
Kaneda
Department of Medicine and Biological Science, Gunma University, Graduate School of Medicine, Gunma, Japan; Education and Research Support Center, Gunma University, Graduate School of Medicine, Gunma, Japan.
Tatsuya
T
Iso
Department of Bioimaging Information Analysis, Gunma University, Graduate School of Medicine, Gunma, Japan.
Aiko
A
Yamaguchi
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Jin
J
Endo
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Yoshinori
Y
Katsumata
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Anzai
A
Atsushi
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Tsunehisa
T
Yamamoto
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Kohsuke
K
Shirakawa
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Xiaoxiang
X
Yan
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Ken
K
Shinmura
Department of Biochemistry, Keio University, School of Medicine, Tokyo, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo, Japan.
Makoto
M
Suematsu
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Keiichi
K
Fukuda
Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan. Electronic address: msano@a8.keio.jp.
Motoaki
M
Sano
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010766:Phosphorylation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D014158:Transcription, Genetic; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000235:genetics*
D006657:Histones; D011768:Pyruvate Dehydrogenase Complex; C029131:pyruvate dehydrogenase activator; D000105:Acetyl Coenzyme A; D003999:Dichloroacetic Acid; D020155:3-Hydroxybutyric Acid
Acetylation; Ketone; Metabolic modulation therapy; Metabolomics