Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems.
Although nitrite (NO(2)(-)) and nitrate (NO(3)(-)) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that NO(2)(-) represents an important source of NO for processes ranging from angiogenesis through hypoxic vasodilation to ischemic organ pr...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2008
|
| _version_ | 1826287716783882240 |
|---|---|
| author | Feelisch, M Fernandez, B Bryan, N Garcia-Saura, M Bauer, S Whitlock, DR Ford, P Janero, DR Rodriguez, J Ashrafian, H |
| author_facet | Feelisch, M Fernandez, B Bryan, N Garcia-Saura, M Bauer, S Whitlock, DR Ford, P Janero, DR Rodriguez, J Ashrafian, H |
| author_sort | Feelisch, M |
| collection | OXFORD |
| description | Although nitrite (NO(2)(-)) and nitrate (NO(3)(-)) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that NO(2)(-) represents an important source of NO for processes ranging from angiogenesis through hypoxic vasodilation to ischemic organ protection. Despite intense investigation, the mechanisms through which NO(2)(-) exerts its physiological/pharmacological effects remain incompletely understood. We sought to systematically investigate the fate of NO(2)(-) in hypoxia from cellular uptake in vitro to tissue utilization in vivo using the Wistar rat as a mammalian model. We find that most tissues (except erythrocytes) produce free NO at rates that are maximal under hypoxia and that correlate robustly with each tissue's capacity for mitochondrial oxygen consumption. By comparing the kinetics of NO release before and after ferricyanide addition in tissue homogenates to mathematical models of NO(2)(-) reduction/NO scavenging, we show that the amount of nitrosylated products formed greatly exceeds what can be accounted for by NO trapping. This difference suggests that such products are formed directly from NO(2)(-), without passing through the intermediacy of free NO. Inhibitor and subcellular fractionation studies indicate that NO(2)(-) reductase activity involves multiple redundant enzymatic systems (i.e. heme, iron-sulfur cluster, and molybdenum-based reductases) distributed throughout different cellular compartments and acting in concert to elicit NO signaling. These observations hint at conserved roles for the NO(2)(-)-NO pool in cellular processes such as oxygen-sensing and oxygen-dependent modulation of intermediary metabolism. |
| first_indexed | 2024-03-07T02:02:50Z |
| format | Journal article |
| id | oxford-uuid:9df2d803-3569-4857-a232-3b220100a780 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:02:50Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:9df2d803-3569-4857-a232-3b220100a7802022-03-27T00:46:44ZTissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9df2d803-3569-4857-a232-3b220100a780EnglishSymplectic Elements at Oxford2008Feelisch, MFernandez, BBryan, NGarcia-Saura, MBauer, SWhitlock, DRFord, PJanero, DRRodriguez, JAshrafian, HAlthough nitrite (NO(2)(-)) and nitrate (NO(3)(-)) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that NO(2)(-) represents an important source of NO for processes ranging from angiogenesis through hypoxic vasodilation to ischemic organ protection. Despite intense investigation, the mechanisms through which NO(2)(-) exerts its physiological/pharmacological effects remain incompletely understood. We sought to systematically investigate the fate of NO(2)(-) in hypoxia from cellular uptake in vitro to tissue utilization in vivo using the Wistar rat as a mammalian model. We find that most tissues (except erythrocytes) produce free NO at rates that are maximal under hypoxia and that correlate robustly with each tissue's capacity for mitochondrial oxygen consumption. By comparing the kinetics of NO release before and after ferricyanide addition in tissue homogenates to mathematical models of NO(2)(-) reduction/NO scavenging, we show that the amount of nitrosylated products formed greatly exceeds what can be accounted for by NO trapping. This difference suggests that such products are formed directly from NO(2)(-), without passing through the intermediacy of free NO. Inhibitor and subcellular fractionation studies indicate that NO(2)(-) reductase activity involves multiple redundant enzymatic systems (i.e. heme, iron-sulfur cluster, and molybdenum-based reductases) distributed throughout different cellular compartments and acting in concert to elicit NO signaling. These observations hint at conserved roles for the NO(2)(-)-NO pool in cellular processes such as oxygen-sensing and oxygen-dependent modulation of intermediary metabolism. |
| spellingShingle | Feelisch, M Fernandez, B Bryan, N Garcia-Saura, M Bauer, S Whitlock, DR Ford, P Janero, DR Rodriguez, J Ashrafian, H Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. |
| title | Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. |
| title_full | Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. |
| title_fullStr | Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. |
| title_full_unstemmed | Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. |
| title_short | Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. |
| title_sort | tissue processing of nitrite in hypoxia an intricate interplay of nitric oxide generating and scavenging systems |
| work_keys_str_mv | AT feelischm tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT fernandezb tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT bryann tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT garciasauram tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT bauers tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT whitlockdr tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT fordp tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT janerodr tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT rodriguezj tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems AT ashrafianh tissueprocessingofnitriteinhypoxiaanintricateinterplayofnitricoxidegeneratingandscavengingsystems |