611
IRUS Total
Downloads
  Altmetric

Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients

File Description SizeFormat 
aao4583_ArticleContent_accepted version sept 2017.docxAccepted version184.23 kBMicrosoft WordView/Open
Title: Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients
Authors: Michelakis, ED
Gurtu, V
Webster, L
Barnes, G
Watson, G
Howard, L
Cupitt, J
Paterson, I
Thompson, RB
Chow, K
O'Regan, DP
Zhao, L
Wharton, J
Kiely, DG
Kinnaird, A
Boukouris, AE
White, C
Nagendran, J
Freed, DH
Wort, SJ
Gibbs, JSR
Wilkins, MR
Item Type: Journal Article
Abstract: Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
Issue Date: 25-Oct-2017
Date of Acceptance: 22-Sep-2017
URI: http://hdl.handle.net/10044/1/52488
DOI: 10.1126/scitranslmed.aao4583
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science
Start Page: 1
End Page: 13
Journal / Book Title: Science Translational Medicine
Volume: 9
Issue: 413
Copyright Statement: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License.
Sponsor/Funder: Medical Research Council (MRC)
British Heart Foundation
British Heart Foundation
Funder's Grant Number: G0701637
PG/14/88/31183
PG/12/61/29818
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
CONGENITAL LACTIC-ACIDOSIS
FAWN-HOODED RATS
COMMON POLYMORPHISM
DICHLOROACETATE DCA
COLORECTAL-CANCER
DEFICIENCY
MITOCHONDRIA
COMPLEX
THERAPY
HYPOXIA
Administration, Oral
Adolescent
Adult
Biomarkers
Dichloroacetic Acid
Familial Primary Pulmonary Hypertension
Female
Genetic Predisposition to Disease
Hemodynamics
Humans
Lung
Male
Middle Aged
Perfusion
Protein Kinase Inhibitors
Protein-Serine-Threonine Kinases
Pulmonary Artery
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Sirtuin 3
Uncoupling Protein 2
Up-Regulation
Young Adult
Lung
Pulmonary Artery
Humans
Genetic Predisposition to Disease
Protein-Serine-Threonine Kinases
Protein Kinase Inhibitors
Administration, Oral
Perfusion
Up-Regulation
Adolescent
Adult
Middle Aged
Female
Male
Hemodynamics
Young Adult
Sirtuin 3
Dichloroacetic Acid
Familial Primary Pulmonary Hypertension
Biomarkers
Uncoupling Protein 2
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Article Number: eaao4583
Online Publication Date: 2017-10-25
Appears in Collections:National Heart and Lung Institute
Institute of Clinical Sciences
Faculty of Medicine