Journal of Molecular Medicine

, Volume 91, Issue 3, pp 333–346 | Cite as

FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate

  • Lin Piao
  • Vaninder K. Sidhu
  • Yong-Hu Fang
  • John J. Ryan
  • Kishan S. Parikh
  • Zhigang Hong
  • Peter T. Toth
  • Erik Morrow
  • Shelby Kutty
  • Gary D. Lopaschuk
  • Stephen L. Archer
Original Article

Abstract

Pyruvate dehydrogenase kinase (PDK) is activated in right ventricular hypertrophy (RVH), causing an increase in glycolysis relative to glucose oxidation that impairs right ventricular function. The stimulus for PDK upregulation, its isoform specificity, and the long-term effects of PDK inhibition are unknown. We hypothesize that FOXO1-mediated PDK4 upregulation causes bioenergetic impairment and RV dysfunction, which can be reversed by dichloroacetate. Adult male Fawn-Hooded rats (FHR) with pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH; age 6–12 months) were compared to age-matched controls. Glucose oxidation (GO) and fatty acid oxidation (FAO) were measured at baseline and after acute dichloroacetate (1 mM × 40 min) in isolated working hearts and in freshly dispersed RV myocytes. The effects of chronic dichloroacetate (0.75 g/L drinking water for 6 months) on cardiac output (CO) and exercise capacity were measured in vivo. Expression of PDK4 and its regulatory transcription factor, FOXO1, were also measured in FHR and RV specimens from PAH patients (n = 10). Microarray analysis of 168 genes related to glucose or FA metabolism showed >4-fold upregulation of PDK4, aldolase B, and acyl-coenzyme A oxidase. FOXO1 was increased in FHR RV, whereas HIF-1α was unaltered. PDK4 expression was increased, and the inactivated form of FOXO1 decreased in human PAH RV (P < 0.01). Pyruvate dehydrogenase (PDH) inhibition in RVH increased proton production and reduced GO’s contribution to the tricarboxylic acid (TCA) cycle. Acutely, dichloroacetate reduced RV proton production and increased GO’s contribution (relative to FAO) to the TCA cycle and ATP production in FHR (P < 0.01). Chronically dichloroacetate decreased PDK4 and FOXO1, thereby activating PDH and increasing GO in FHR. These metabolic changes increased CO (84 ± 14 vs. 69 ± 14 ml/min, P < 0.05) and treadmill-walking distance (239 ± 20 vs. 171 ± 22 m, P < 0.05). Chronic dichloroacetate inhibits FOXO1-induced PDK4 upregulation and restores GO, leading to improved bioenergetics and RV function in RVH.

Keywords

Glycolysis HIF-1α Aldolase B FOXO3 Acyl-coenzyme A oxidase 2 

Notes

Acknowledgments

This work is supported by NIH-RO1-HL071115 and 1RC1HL099462-01.

Disclosures

None

Supplementary material

109_2012_982_MOESM1_ESM.pdf (995 kb)
ESM 1(PDF 994 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Lin Piao
    • 1
  • Vaninder K. Sidhu
    • 2
  • Yong-Hu Fang
    • 1
  • John J. Ryan
    • 1
  • Kishan S. Parikh
    • 1
  • Zhigang Hong
    • 1
  • Peter T. Toth
    • 1
  • Erik Morrow
    • 1
  • Shelby Kutty
    • 3
  • Gary D. Lopaschuk
    • 2
  • Stephen L. Archer
    • 1
    • 4
  1. 1.Section of Cardiology, Department of MedicineUniversity of ChicagoChicagoUSA
  2. 2.Cardiovascular Research Centre, Mazankowski Alberta Heart InstituteUniversity of AlbertaEdmontonCanada
  3. 3.Joint Division of Pediatric Cardiology, Children’s Hospital and Medical CenterUniversity of NebraskaOmahaUSA
  4. 4.Department of MedicineQueen’s University KingstonKingstonCanada

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