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

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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.

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References

  1. Bichel T, Spahr-Schopfer I, Berner M, Jaeggi E, Velkovski Y, Friedli B, Kalangos A, Faidutti B, Rouge JC (1997) Successful weaning from cardiopulmonary bypass after cardiac surgery using inhaled nitric oxide. Paediatr Anaesth 7:335–339

    Article  PubMed  CAS  Google Scholar 

  2. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK et al (2006) An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113:2630–2641

    Article  PubMed  CAS  Google Scholar 

  3. Pelouch V, Kolar F, Ost'adal B, Milerova M, Cihak R, Widimsky J (1997) Regression of chronic hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and fibrosis: effect of enalapril. Cardiovasc Drugs Ther 11:177–185

    Article  PubMed  CAS  Google Scholar 

  4. Fang YH, Piao L, Hong Z, Toth PT, Marsboom G, Bache-Wiig P, Rehman J, Archer SL (2012) Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle. J Mol Med (Berl) 90:31–43

    Article  CAS  Google Scholar 

  5. Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88:47–60

    Article  PubMed  CAS  Google Scholar 

  6. Archer SL, Wu XC, Thebaud B, Nsair A, Bonnet S, Tyrrell B, McMurtry MS, Hashimoto K, Harry G, Michelakis ED (2004) Preferential expression and function of voltage-gated, O2-sensitive K+channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells. Circ Res 95:308–318

    Article  PubMed  CAS  Google Scholar 

  7. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL (2002) Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105:244–250

    Article  PubMed  CAS  Google Scholar 

  8. Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J et al (2012) Lung (1)(8)F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185:670–679

    Article  PubMed  CAS  Google Scholar 

  9. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C et al (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci U S A 104:1342–1347

    Article  PubMed  CAS  Google Scholar 

  10. Stacpoole PW (1989) The pharmacology of dichloroacetate. Metabolism 38:1124–1144

    Article  PubMed  CAS  Google Scholar 

  11. Sugden MC, Holness MJ (2003) Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab 284:E855–862

    PubMed  CAS  Google Scholar 

  12. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 329(Pt 1):191–196

    PubMed  CAS  Google Scholar 

  13. Rich S, Pogoriler J, Husain AN, Toth PT, Gomberg-Maitland M, Archer SL (2010) Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest 138:1234–1239

    Article  PubMed  CAS  Google Scholar 

  14. Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J et al (2005) Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol 45:1849–1855

    Article  PubMed  CAS  Google Scholar 

  15. Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl) 88:47–60

    Article  CAS  Google Scholar 

  16. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185

    Article  PubMed  Google Scholar 

  17. Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, Shelton JM, Gerard RD, Rothermel BA, Gillette TG et al (2012) Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 122:1109–1118

    Article  PubMed  CAS  Google Scholar 

  18. Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF (2009) Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 120:1951–1960

    Article  PubMed  Google Scholar 

  19. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN et al (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121:2661–2671

    Article  PubMed  CAS  Google Scholar 

  20. Ryan J, Bloch K, Archer SL (2011) Rodent models of pulmonary hypertension: harmonisation with the world health organisation's categorisation of human PH. Int J Clin Pract 65(Suppl 172):15–34

    Article  Google Scholar 

  21. Rehman J, Archer SL (2010) A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension. Adv Exp Med Biol 661:171–185

    Article  PubMed  CAS  Google Scholar 

  22. Urboniene D, Haber I, Fang YH, Thenappan T, Archer SL (2010) Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 299:L401–412

    Article  PubMed  CAS  Google Scholar 

  23. Puthanveetil P, Wang Y, Wang F, Kim MS, Abrahani A, Rodrigues B (2010) The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis. Endocrinology 151:2306–2318

    Article  PubMed  CAS  Google Scholar 

  24. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN et al (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117:1519–1531

    Article  PubMed  Google Scholar 

  25. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D et al (2011) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31–34

    Google Scholar 

  26. Stanley WC, Hernandez LA, Spires D, Bringas J, Wallace S, McCormack JG (1996) Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate. J Mol Cell Cardiol 28:905–914

    Article  PubMed  CAS  Google Scholar 

  27. Cabrero A, Jove M, Planavila A, Merlos M, Laguna JC, Vazquez-Carrera M (2003) Down-regulation of acyl-CoA oxidase gene expression in heart of troglitazone-treated mice through a mechanism involving chicken ovalbumin upstream promoter transcription factor II. Mol Pharmacol 64:764–772

    Article  PubMed  CAS  Google Scholar 

  28. Millo H, Werman MJ (2000) Hepatic fructose-metabolizing enzymes and related metabolites: role of dietary copper and gender. J Nutr Biochem 11:374–381

    Article  PubMed  CAS  Google Scholar 

  29. Liu J, Wang R, Desai K, Wu L (2011) Upregulation of aldolase B and overproduction of methylglyoxal in vascular tissues from rats with metabolic syndrome. Cardiovasc Res 92:494–503

    Article  PubMed  CAS  Google Scholar 

  30. Treberg JR, MacCormack TJ, Lewis JM, Almeida-Val VM, Val AL, Driedzic WR (2007) Intracellular glucose and binding of hexokinase and phosphofructokinase to particulate fractions increase under hypoxia in heart of the amazonian armored catfish (Liposarcus pardalis). Physiol Biochem Zool 80:542–550

    Article  PubMed  CAS  Google Scholar 

  31. Furuyama T, Kitayama K, Yamashita H, Mori N (2003) Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J 375:365–371

    Article  PubMed  CAS  Google Scholar 

  32. Constantin-Teodosiu D, Constantin D, Stephens F, Laithwaite D, Greenhaff PL (2012) The role of FOXO and PPAR transcription factors in diet-mediated inhibition of PDC activation and carbohydrate oxidation during exercise in humans and the role of pharmacological activation of PDC in overriding these changes. Diabetes 61:1017–1024

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

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

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Authors and Affiliations

  1. Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA

    Lin Piao, Yong-Hu Fang, John J. Ryan, Kishan S. Parikh, Zhigang Hong, Peter T. Toth, Erik Morrow & Stephen L. Archer

  2. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada

    Vaninder K. Sidhu & Gary D. Lopaschuk

  3. Joint Division of Pediatric Cardiology, Children’s Hospital and Medical Center, University of Nebraska, Omaha, USA

    Shelby Kutty

  4. Department of Medicine, Queen’s University Kingston, 94 Stuart St., Room 3041, Etherington Hall, Kingston, ON, K7L 3N6, Canada

    Stephen L. Archer

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  1. Lin Piao
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Correspondence to Stephen L. Archer.

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Piao, L., Sidhu, V.K., Fang, YH. et al. FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med 91, 333–346 (2013). https://doi.org/10.1007/s00109-012-0982-0

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