title: FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate.
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-1 α 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.
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Piao
authors.forename: Vaninder K
authors.initials: VK
authors.lastname: Sidhu
authors.forename: Yong-Hu
authors.initials: YH
authors.lastname: Fang
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Kishan S
authors.initials: KS
authors.lastname: Parikh
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hong
authors.forename: Peter T
authors.initials: PT
authors.lastname: Toth
authors.forename: Erik
authors.initials: E
authors.lastname: Morrow
authors.forename: Shelby
authors.initials: S
authors.lastname: Kutty
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D003999:Dichloroacetic Acid / Q000008:administration & dosage*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010805:Physical Conditioning, Animal; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D018497:Ventricular Dysfunction, Right / Q000378:metabolism / Q000503:physiopathology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C000631432:PDK4 protein, human; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases; D005947:Glucose