Research ArticlePulmonary Arterial Hypertension

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

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Science Translational Medicine  25 Oct 2017:
Vol. 9, Issue 413, eaao4583
DOI: 10.1126/scitranslmed.aao4583

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Progress for PAH

In addition to thickening and occlusion of the pulmonary arteries, mitochondrial respiration is suppressed in pulmonary arterial hypertension (PAH). Michelakis et al. treated lungs from patients with PAH with dichloroacetate (DCA), a drug used to treat cancer and congenital mitochondrial disease that inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA increased mitochondrial function; however, the response was variable, and this variable response was mirrored in a phase 1 trial, with some patients showing improved hemodynamics and functional capacity. The authors determined that patients with inactivating mutations in two genes encoding mitochondrial proteins were less responsive to DCA. This work highlights the importance of considering patient genotype in clinical trial design and identifies a drug target for PAH.

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.

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