Role of endothelial dysfunction in modulating the plasma redox homeostasis in visceral leishmaniasis
Autor: | Tuli Biswas, Avik Sarkar, Gargi Sen, Kaustav Dutta Chowdhury |
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Rok vydání: | 2010 |
Předmět: |
Male
Ceramide Time Factors Endothelium Nitric Oxide Synthase Type III Kupffer Cells Blotting Western Biophysics Biology Pharmacology medicine.disease_cause Ceramides Nitric Oxide Biochemistry Host-Parasite Interactions chemistry.chemical_compound Superoxides Cricetinae medicine Animals Homeostasis Endothelial dysfunction Molecular Biology Cells Cultured chemistry.chemical_classification Reactive oxygen species Glutathione Disulfide Mesocricetus Nitrotyrosine NADPH Oxidases medicine.disease Flow Cytometry Glutathione Endothelial stem cell medicine.anatomical_structure Sphingomyelin Phosphodiesterase chemistry Immunology Leishmaniasis Visceral Endothelium Vascular Oxidoreductases Reactive Oxygen Species Oxidation-Reduction Peroxynitrite Oxidative stress Leishmania donovani |
Zdroj: | Biochimica et biophysica acta. 1810(7) |
ISSN: | 0006-3002 |
Popis: | Background Evidence in the literature suggests that down-regulation of nitric oxide (NO) is associated with the pathophysiological conditions during visceral leishmaniasis (VL). Here we have investigated the mechanism that leads to the down regulation of systemic NO in the infected condition. Moreover, we have determined whether down regulation of NO is associated with increased generation of reactive oxygen species (ROS) during this disease. Therapeutic strategy targeting signaling molecules of these events was evaluated. Methods Plasma protein-nitrotyrosine was examined by ELISA kit. Generation of superoxides and peroxynitrites was investigated by flow cytometry. NO bioavailability in endothelial cells was evaluated using DAF-2DA fluorescence. Ceramide contents were evaluated using FACS analysis, HPTLC and HPLC. Results L. donovani infected reticulo-endothelial cells regulated the activity of eNOS and NAD(P)H oxidase in the endothelial cells through the generation of intercellular messenger, ceramide. Activation of SMases played an important role in the generation of ceramide in animals during chronic infection. These events led to generation of ROS within endothelial cells. Modulation of redox status of plasma and accumulation of ROS in endothelial cells were critically involved in the regulation of NO bioavailability in plasma of the infected animal. Endothelial dysfunction and decline of NO were resulted from an increased production of superoxide where upregulation of eNOS expression appeared as an ineffective compensatory event. Inhibition of ceramide generation increased NO bioavailability, prevented endothelial dysfunction and concomitant oxidative stress. Conclusion and general significance Decreased NO bioavailability and endothelial dysfunction were the downstream of ceramide signaling cascade. ROS accumulation promoted peroxynitrite generation and reduced NO bioavailability. Inhibition of ceramide generation may be a potential therapeutic option in preventing the co-morbidity associated with VL. |
Databáze: | OpenAIRE |
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