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.
Highlights
Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are two forms of pulmonary hypertension (PH) characterized by obstructive vasculopathy
Clinical and haemodynamics characteristics, PH is categorized into five clinical groups: pulmonary arterial hypertension (PAH); PH due to left heart disease; PH associated with lung disease and/or hypoxia; chronic thromboembolic pulmonary hypertension (CTEPH) and PH with unclear or multifactorial mechanisms[2]
A substantially different metabolic profile at the level of glycolysis, oxidative phosphorylation and glutamine metabolism is present in PAH-endothelial cells (ECs) compared to CTEPH-EC and suggests differences in molecular mechanisms and regulatory pathways that could be important in the disease pathology and treatment
Summary
Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are two forms of pulmonary hypertension (PH) characterized by obstructive vasculopathy. Abbreviations ATP Adenosine triphosphate α-SMA Alpha-smooth muscle actin BPTES Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)-ethyl-sulfide Ct Threshold cycle CTEPH Chronic thromboembolic pulmonary hypertension CTEPH-EC Chronic thromboembolic pulmonary hypertension endothelial cells DCA Dichloroacetate ECs Endothelial cells eNOS Endothelial nitric oxide synthase FBS Fetal bovine serum GLS1 Glutaminase 1 GLUD1 Glutamate-dehydrogenase-1 GLUT1 Glucose transporter 1 G6PD Glucose-6-phosphate-dehydrogenase HK2 Hexokinase 2 HMVEC-L Human lung microvascular endothelial cells HOXD Homeobox D cluster HPAEC Human pulmonary artery endothelial cells LDHA Lactate dehydrogenase A mPAP Mean pulmonary arterial pressure PAH Pulmonary arterial hypertension PAH-EC Pulmonary arterial hypertension endothelial cells PDK Pyruvate dehydrogenase kinase PDHA1 Pyruvate dehydrogenase subunit E1 alpha PEA Pulmonary endarterectomy PFKFB3 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 PH Pulmonary hypertension PPP Pentose phosphate pathway UK-5099 2-Cyano-3-(1-phenyl-1H-indol-3-yl)-2-propenoic-acid 3-PO 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one. Even though endothelial cells (ECs) mainly rely on glycolysis for adenosine triphosphate (ATP) production, mitochondria remain fully functional and rather works as suppliers for cellular building blocks through metabolism of amino acids such as glutamine and glutamate that serve as biosynthetic precursors to produce nucleotides and macromolecules through g lutaminolysis[9]
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