FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right vent
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ORIGINAL ARTICLE
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 Received: 10 September 2012 / Revised: 25 October 2012 / Accepted: 7 November 2012 / Published online: 18 December 2012 # Springer-Verlag Berlin Heidelberg 2012
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 Electronic supplementary material The online version of this article (doi:10.1007/s00109-012-0982-0) contains supplementary material, which is available to authorized users. L. Piao : Y.-H. Fang : J. J. Ryan : K. S. Parikh : Z. Hong : P. T. Toth : E. Morrow : S. L. Archer Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA V. K. Sidhu : G. D. Lopaschuk Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada S. Kutty Joint Division of Pediatric Cardiology, Children’s Hospital and Medical Center, University of Nebraska, Omaha, USA S. L. Archer (*) Department of Medicine, Queen’s University Kingston, 94 Stuart St., Room 3041, Etherington Hall, Kingston, ON K7L 3N6, Canada e-mail: [email protected]
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 (n010). 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
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