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Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E

1
Department of Pharmacology, College of Pharmacy Sciences, University of Hail, 55476 Hail, Saudi Arabia
2
Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
*
Author to whom correspondence should be addressed.
Metabolites 2018, 8(4), 87; https://doi.org/10.3390/metabo8040087
Received: 8 November 2018 / Revised: 27 November 2018 / Accepted: 28 November 2018 / Published: 30 November 2018
Pulmonary arterial hypertension (PAH) is a multi-factorial disease characterized by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Excessive reactive oxygen species (ROS) formation resulted in alterations of the structure and function of pulmonary arterial walls, leading to right ventricular failure and death. Diabetes mellitus has not yet been implicated in pulmonary hypertension. However, recently, variable studies have shown that diabetes is correlated with pulmonary hypertension pathobiology, which could participate in the modification of pulmonary artery muscles. The metabolomic changes in PASMCs were studied in response to 25 mM of D-glucose (high glucose, or HG) in order to establish a diabetic-like condition in an in vitro setting, and compared to five mM of D-glucose (normal glucose, or LG). The effect of co-culturing these cells with an ideal blood serum concentration of cholecalciferol-D3 and tocopherol was also examined. The current study aimed to examine the role of hyperglycemia in pulmonary arterial hypertension by the quantification and detection of the metabolomic alteration of smooth muscle cells in high-glucose conditions. Untargeted metabolomics was carried out using hydrophilic interaction liquid chromatography and high-resolution mass spectrometry. Cell proliferation was assessed by cell viability and the [3H] thymidine incorporation assay, and the redox state within the cells was examined by measuring reactive oxygen species (ROS) generation. The results demonstrated that PASMCs in high glucose (HG) grew, proliferated faster, and generated higher levels of superoxide anion (O2·) and hydrogen peroxide (H2O2). The metabolomics of cells cultured in HG showed that the carbohydrate pathway, especially that of the upper glycolytic pathway metabolites, was influenced by the activation of the oxidation pathway: the pentose phosphate pathway (PPP). The amount of amino acids such as aspartate and glutathione reduced via HG, while glutathione disulfide, N6-Acetyl-L-lysine, glutamate, and 5-aminopentanoate increased. Lipids either as fatty acids or glycerophospholipids were downregulated in most of the metabolites, with the exception of docosatetraenoic acid and PG (16:0/16:1(9Z)). Purine and pyrimidine were influenced by hyperglycaemia following PPP oxidation. The results in addition showed that cells exposed to 25 mM of glucose were oxidatively stressed comparing to those cultured in five mM of glucose. Cholecalciferol (D3, or vitamin D) and tocopherol (vitamin E) were shown to restore the redox status of many metabolic pathways. View Full-Text
Keywords: oxidative stress; pulmonary arterial hypertension; smooth muscle cells; metabolomics; metabolic profiling; diabetes mellitus; hyperglycaemia; vitamin D; vitamin E oxidative stress; pulmonary arterial hypertension; smooth muscle cells; metabolomics; metabolic profiling; diabetes mellitus; hyperglycaemia; vitamin D; vitamin E
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MDPI and ACS Style

Alamri, A.; Burzangi, A.S.; Coats, P.; Watson, D.G. Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E. Metabolites 2018, 8, 87. https://doi.org/10.3390/metabo8040087

AMA Style

Alamri A, Burzangi AS, Coats P, Watson DG. Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E. Metabolites. 2018; 8(4):87. https://doi.org/10.3390/metabo8040087

Chicago/Turabian Style

Alamri, Abdulwahab, Abdulhadi S. Burzangi, Paul Coats, and David G. Watson 2018. "Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E" Metabolites 8, no. 4: 87. https://doi.org/10.3390/metabo8040087

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