04 February 2019

Decreased glycolysis as metabolic footprint of endothelial cells in chronic thromboembolic pulmonary hypertension

Background: 

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by non-resolution of thrombi that obstruct main pulmonary arteries and secondary cause vascular remodeling of the pulmonary vasculature. Endothelial cells (EC) lining the vascular wall are an important component in vascular disease development. We speculated that metabolic dysregulation of EC contribute to cellular changes that promote vascular remodeling in CTEPH.

Methods:

This study used endothelial cells (EC-CTEPH, n=12) isolated from specimen extracted at pulmonary endarterectomy.1 Healthy human pulmonary artery endothelial (HPAE) cells were used as control group in all experiments performed. Expression levels of metabolic enzymes were studied at mRNA and protein level by RT-PCR and western blot, respectively. Glucose consumption and lactate production was measured in the supernatant overlying EC-CTEPH and HPAE using BGEM test cards.

Results:

Results are summarized in Table 1. EC-CTEPH showed significantly lower mRNA levels of all glycolytic enzymes analyzed compared to HPAE. Additionally, protein levels of HK2, PFKFB3 and LDH-a were reduced in EC-CTEPH compared to HPAE. Transcript levels of PDK1, inhibitor of PDHA1, and GLUD1, involved in glutamine metabolism, were also downregulated. Fatty acid and pentose phosphate metabolism did not present significant differences between EC-CTEPH and HPAE. A lower glycolytic flux in EC-CTEPH, when compared to HPAE, was observed in terms of glucose consumption (52.9±20.3 vs 44.5±21.4 mg/dL of glucose not consumed)† and lactate production (8.4±2.0 vs 9.3±1.5 mmol/L)†, although no statistical significance was reached.

 

49 table.PNG

Conclusion:

Our results showed that EC in human CTEPH present a reduced glycolytic metabolism compared to healthy EC. TCA and glutamine metabolism were also downregulated in EC-CTEPH. Other metabolic pathways such as FAO and PPP did not show a compensatory upregulation. More studies need to be performed to determine the role of our findings in EC-CTEPH pathogenesis.

 

1 Tura-Ceide et al. European Respiratory Journal, 48 (suppl 60) 2016. PA3606
Supported by grants H2020-Marie SkƗodowska-Curie ITN (No. 675527), SEPAR (188/2013,164/2016), SOCAP, FCHP, Fondo de Investigación
Sanitaria (PI15/00582), Miguel Servet by Instituto de Salud Carlos III (CP17/00114) (OTC).

 

Key Contributors

Valérie F. Smolders 1-3, C. Rodríguez 1, I. Blanco 1,4, J. Osorio 1,4, L. Piccari 1, C. Bonjoch 1, P.H.A. Quax 3, M. Cascante 1,2, V. I Peinado 1,4, M. Castellà 5, Joan Albert Barberà 1,4, O. Tura-Ceide 1,4 : 1 Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. 2 Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 643, Barcelona, Spain. 3 Department of Vascular Surgery, LUMC, Leiden, The Netherlands. 4 Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Madrid, Spain. 5 Department of Cardiovascular Surgery, Institut Clínic del Tòrax, Hospital Clínic, University of Barcelona, Spain.


Comments (0)

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI
standard-example-image.jpg