Dataset Information

Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase.

ABSTRACT: Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of 15N3-GTN into 15N-nitrite. We performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C (ascorbic acid). Metabolomics analyses revealed that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated xanthine oxidase (XO), an enzyme that is critical for the metabolic bioactivation of GTN into NO. Ascorbic acid prevented inactivation of XO, resulting in increased NO production from GTN. Our studies suggest that ascorbic acid has the ability to prevent nitrate tolerance by protecting XO, but not aldehyde dehydrogenase (another GTN bioactivating enzyme), from GTN-induced inactivation. Our findings provide a mechanistic explanation for the previously observed beneficial effects of ascorbic acid in nitrate therapy.

SUBMITTER: Axton ER

PROVIDER: S-EPMC6167911 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase.

Axton Elizabeth Rose ER Cristobal Eleonso E Choi Jaewoo J Miranda Cristobal L CL Stevens Jan Frederik JF

Frontiers in pharmacology 20180925

Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We devel ...[more]

PMID: 30319419

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Project description:Freeze-thaw stress is one of the major environmental constraints that limit plant growth and reduce productivity and quality. Plants exhibit a variety of cellular dysfunctions following freeze-thaw stress, including accumulation of reactive oxygen species (ROS). This means that enhancement of antioxidant capacity by exogenous application of antioxidants could potentially be one of the strategies for improving freezing tolerance (FT) of plants. Exogenous application of ascorbic acid (AsA), as an antioxidant, has been shown to improve plant tolerance against abiotic stresses but its effect on FT has not been investigated. We evaluated the effect of AsA-feeding on FT of spinach (Spinacia oleracea L.) at whole plant and excised-leaf level, and conducted metabolite profiling of leaves before and after AsA treatment to explore metabolic explanation for change in FT. AsA application did not impede leaf growth, instead slightly promoted it. Temperature-controlled freeze-thaw tests revealed AsA-fed plants were more freezing tolerant as indicated by: (a) less visual damage/mortality; (b) lower ion leakage; and (c) less oxidative injury, lower abundance of free radicals ( O2·- and H2O2). Comparative leaf metabolite profiling revealed clear separation of metabolic phenotypes for control versus AsA-fed leaves. Specifically, AsA-fed leaves had greater abundance of antioxidants (AsA, glutathione, alpha- & gamma-tocopherol) and compatible solutes (proline, galactinol, and myo-inositol). AsA-fed leaves also had higher activity of antioxidant enzymes (superoxide dismutase, ascorbate peroxidase, and catalase). These changes, together, may improve FT via alleviating freeze-induced oxidative stress as well as protecting membranes from freeze desiccation. Additionally, improved FT by AsA-feeding may potentially include enhanced cell wall/lignin augmentation and bolstered secondary metabolism as indicated by diminished level of phenylalanine and increased abundance of branched amino acids, respectively.

Dataset Information

Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase.

Publications

Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase.

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