Imperial College London
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Professor Martin Wilkins

Faculty of Medicine, National Heart & Lung Institute

Professor of Clinical Pharmacology
 
 
 
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Contact

 

+44 (0)20 3313 6101m.wilkins Website

 
 
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Assistant

 

Mrs Elizabeth O'Brien +44 (0)20 3313 6101

 
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Location

 

NIHR Imperial Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Michelakis:2017:10.1126/scitranslmed.aao4583,
author = {Michelakis, ED and Gurtu, V and Webster, L and Barnes, G and Watson, G and Howard, L and Cupitt, J and Paterson, I and Thompson, RB and Chow, K and O'Regan, DP and Zhao, L and Wharton, J and Kiely, DG and Kinnaird, A and Boukouris, AE and White, C and Nagendran, J and Freed, DH and Wort, SJ and Gibbs, JSR and Wilkins, MR},
doi = {10.1126/scitranslmed.aao4583},
journal = {Science Translational Medicine},
pages = {1--13},
title = {Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients},
url = {http://dx.doi.org/10.1126/scitranslmed.aao4583},
volume = {9},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Michelakis,ED
AU  - Gurtu,V
AU  - Webster,L
AU  - Barnes,G
AU  - Watson,G
AU  - Howard,L
AU  - Cupitt,J
AU  - Paterson,I
AU  - Thompson,RB
AU  - Chow,K
AU  - O'Regan,DP
AU  - Zhao,L
AU  - Wharton,J
AU  - Kiely,DG
AU  - Kinnaird,A
AU  - Boukouris,AE
AU  - White,C
AU  - Nagendran,J
AU  - Freed,DH
AU  - Wort,SJ
AU  - Gibbs,JSR
AU  - Wilkins,MR
DO  - 10.1126/scitranslmed.aao4583
EP  - 13
PY  - 2017///
SN  - 1946-6234
SP  - 1
TI  - Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients
T2  - Science Translational Medicine
UR  - http://dx.doi.org/10.1126/scitranslmed.aao4583
UR  - http://stm.sciencemag.org/cgi/content/full/9/413/eaao4583?ijkey=uKXuyKLaY7nII&keytype=ref&siteid=scitransmed
UR  - https://stm.sciencemag.org/content/9/413/eaao4583/
UR  - http://hdl.handle.net/10044/1/52488
VL  - 9
ER  -
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