Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension

V F E D Smolders; I Blanco; R Szulcek; Wim Timens; L Piccari; Y Roger; X Hu; Constanza Morén; C Bonjoch; L Sebastián; M Castellà; J Osorio; V I Peinado; Harm Jan Bogaard; P H A Quax; M Cascante; J A Barberà; O Tura-Ceide

doi:10.1038/s41598-022-06238-z

Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension

V F E D Smolders, I Blanco, R Szulcek, Wim Timens, L Piccari, Y Roger, X Hu, Constanza Morén, C Bonjoch, L Sebastián, M Castellà, J Osorio, V I Peinado, Harm Jan Bogaard, P H A Quax, M Cascante^*, J A Barberà^*, O Tura-Ceide^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are two forms of pulmonary hypertension (PH) characterized by obstructive vasculopathy. Endothelial dysfunction along with metabolic changes towards increased glycolysis are important in PAH pathophysiology. Less is known about such abnormalities in endothelial cells (ECs) from CTEPH patients. This study provides a systematic metabolic comparison of ECs derived from CTEPH and PAH patients. Metabolic gene expression was studied using qPCR in cultured CTEPH-EC and PAH-EC. Western blot analyses were done for HK2, LDHA, PDHA1, PDK and G6PD. Basal viability of CTEPH-EC and PAH-EC with the incubation with metabolic inhibitors was measured using colorimetric viability assays. Human pulmonary artery endothelial cells (HPAEC) were used as healthy controls. Whereas PAH-EC showed significant higher mRNA levels of GLUT1, HK2, LDHA, PDHA1 and GLUD1 metabolic enzymes compared to HPAEC, CTEPH-EC did not. Oxidative phosphorylation associated proteins had an increased expression in PAH-EC compared to CTEPH-EC and HPAEC. PAH-EC, CTEPH-EC and HPAEC presented similar HOXD macrovascular gene expression. Metabolic inhibitors showed a dose-dependent reduction in viability in all three groups, predominantly in PAH-EC. A different metabolic profile is present in CTEPH-EC compared to PAH-EC and suggests differences in molecular mechanisms important in the disease pathology and treatment.

Original language	English
Article number	2283
Pages (from-to)	2283
Number of pages	12
Journal	Scientific Reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-06238-z
Publication status	Published - Dec-2022

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Smolders, V. F. E. D., Blanco, I., Szulcek, R., Timens, W., Piccari, L., Roger, Y., Hu, X., Morén, C., Bonjoch, C., Sebastián, L., Castellà, M., Osorio, J., Peinado, V. I., Bogaard, H. J., Quax, P. H. A., Cascante, M., Barberà, J. A., & Tura-Ceide, O. (2022). Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. Scientific Reports, 12(1), 2283. Article 2283. https://doi.org/10.1038/s41598-022-06238-z

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title = "Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension",

abstract = "Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are two forms of pulmonary hypertension (PH) characterized by obstructive vasculopathy. Endothelial dysfunction along with metabolic changes towards increased glycolysis are important in PAH pathophysiology. Less is known about such abnormalities in endothelial cells (ECs) from CTEPH patients. This study provides a systematic metabolic comparison of ECs derived from CTEPH and PAH patients. Metabolic gene expression was studied using qPCR in cultured CTEPH-EC and PAH-EC. Western blot analyses were done for HK2, LDHA, PDHA1, PDK and G6PD. Basal viability of CTEPH-EC and PAH-EC with the incubation with metabolic inhibitors was measured using colorimetric viability assays. Human pulmonary artery endothelial cells (HPAEC) were used as healthy controls. Whereas PAH-EC showed significant higher mRNA levels of GLUT1, HK2, LDHA, PDHA1 and GLUD1 metabolic enzymes compared to HPAEC, CTEPH-EC did not. Oxidative phosphorylation associated proteins had an increased expression in PAH-EC compared to CTEPH-EC and HPAEC. PAH-EC, CTEPH-EC and HPAEC presented similar HOXD macrovascular gene expression. Metabolic inhibitors showed a dose-dependent reduction in viability in all three groups, predominantly in PAH-EC. A different metabolic profile is present in CTEPH-EC compared to PAH-EC and suggests differences in molecular mechanisms important in the disease pathology and treatment.",

author = "Smolders, {V F E D} and I Blanco and R Szulcek and Wim Timens and L Piccari and Y Roger and X Hu and Constanza Mor{\'e}n and C Bonjoch and L Sebasti{\'a}n and M Castell{\`a} and J Osorio and Peinado, {V I} and Bogaard, {Harm Jan} and Quax, {P H A} and M Cascante and Barber{\`a}, {J A} and O Tura-Ceide",

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

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doi = "10.1038/s41598-022-06238-z",

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Smolders, VFED, Blanco, I, Szulcek, R, Timens, W, Piccari, L, Roger, Y, Hu, X, Morén, C, Bonjoch, C, Sebastián, L, Castellà, M, Osorio, J, Peinado, VI, Bogaard, HJ, Quax, PHA, Cascante, M, Barberà, JA & Tura-Ceide, O 2022, 'Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension', Scientific Reports, vol. 12, no. 1, 2283, pp. 2283. https://doi.org/10.1038/s41598-022-06238-z

TY - JOUR

T1 - Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension

AU - Smolders, V F E D

AU - Blanco, I

AU - Szulcek, R

AU - Timens, Wim

AU - Piccari, L

AU - Roger, Y

AU - Hu, X

AU - Morén, Constanza

AU - Bonjoch, C

AU - Sebastián, L

AU - Castellà, M

AU - Osorio, J

AU - Peinado, V I

AU - Bogaard, Harm Jan

AU - Quax, P H A

AU - Cascante, M

AU - Barberà, J A

AU - Tura-Ceide, O

PY - 2022/12

Y1 - 2022/12

N2 - Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are two forms of pulmonary hypertension (PH) characterized by obstructive vasculopathy. Endothelial dysfunction along with metabolic changes towards increased glycolysis are important in PAH pathophysiology. Less is known about such abnormalities in endothelial cells (ECs) from CTEPH patients. This study provides a systematic metabolic comparison of ECs derived from CTEPH and PAH patients. Metabolic gene expression was studied using qPCR in cultured CTEPH-EC and PAH-EC. Western blot analyses were done for HK2, LDHA, PDHA1, PDK and G6PD. Basal viability of CTEPH-EC and PAH-EC with the incubation with metabolic inhibitors was measured using colorimetric viability assays. Human pulmonary artery endothelial cells (HPAEC) were used as healthy controls. Whereas PAH-EC showed significant higher mRNA levels of GLUT1, HK2, LDHA, PDHA1 and GLUD1 metabolic enzymes compared to HPAEC, CTEPH-EC did not. Oxidative phosphorylation associated proteins had an increased expression in PAH-EC compared to CTEPH-EC and HPAEC. PAH-EC, CTEPH-EC and HPAEC presented similar HOXD macrovascular gene expression. Metabolic inhibitors showed a dose-dependent reduction in viability in all three groups, predominantly in PAH-EC. A different metabolic profile is present in CTEPH-EC compared to PAH-EC and suggests differences in molecular mechanisms important in the disease pathology and treatment.

AB - Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are two forms of pulmonary hypertension (PH) characterized by obstructive vasculopathy. Endothelial dysfunction along with metabolic changes towards increased glycolysis are important in PAH pathophysiology. Less is known about such abnormalities in endothelial cells (ECs) from CTEPH patients. This study provides a systematic metabolic comparison of ECs derived from CTEPH and PAH patients. Metabolic gene expression was studied using qPCR in cultured CTEPH-EC and PAH-EC. Western blot analyses were done for HK2, LDHA, PDHA1, PDK and G6PD. Basal viability of CTEPH-EC and PAH-EC with the incubation with metabolic inhibitors was measured using colorimetric viability assays. Human pulmonary artery endothelial cells (HPAEC) were used as healthy controls. Whereas PAH-EC showed significant higher mRNA levels of GLUT1, HK2, LDHA, PDHA1 and GLUD1 metabolic enzymes compared to HPAEC, CTEPH-EC did not. Oxidative phosphorylation associated proteins had an increased expression in PAH-EC compared to CTEPH-EC and HPAEC. PAH-EC, CTEPH-EC and HPAEC presented similar HOXD macrovascular gene expression. Metabolic inhibitors showed a dose-dependent reduction in viability in all three groups, predominantly in PAH-EC. A different metabolic profile is present in CTEPH-EC compared to PAH-EC and suggests differences in molecular mechanisms important in the disease pathology and treatment.

U2 - 10.1038/s41598-022-06238-z

DO - 10.1038/s41598-022-06238-z

M3 - Article

C2 - 35145193

SN - 2045-2322

VL - 12

SP - 2283

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 2283

ER -

Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension

Abstract

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