Proceedings of the National Academy of Sciences - PNAS, 2008-07, Vol.105 (29), p.10256-10261
2008
Details
- Autor(en) / Beteiligte
- Titel
- Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2008-07, Vol.105 (29), p.10256-10261
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2008
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The nitrite anion is reduced to nitric oxide (NO{bullet}) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO{bullet} signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type (⁺/⁺) and knockout (⁻/⁻) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO{bullet} generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO{bullet} generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO{bullet} by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin⁺/⁺ but not in myoglobin⁻/⁻ hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin⁺/⁺ mice, whereas in myoglobin⁻/⁻ mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0801336105Titel-ID: cdi_pnas_primary_105_29_10256
- Format
- –
- Schlagworte
- Aconitate Hydratase - antagonists & inhibitors, Animals, Biological Sciences, Cell Respiration - physiology, Cell Survival - physiology, Cells, Heart, Heart attacks, Heme - metabolism, Hypoxia, In Vitro Techniques, Ischemia, Male, Mice, Mice, Knockout, Mitochondria, Heart - metabolism, Myocardial Infarction - prevention & control, Myocardial reperfusion, Myocardial Reperfusion Injury - drug therapy, Myocardial Reperfusion Injury - genetics, Myocardial Reperfusion Injury - metabolism, Myocardial Reperfusion Injury - pathology, Myocardium - metabolism, Myocardium - pathology, Myoglobin - deficiency, Myoglobin - genetics, Myoglobin - metabolism, Nitrate Reductase - deficiency, Nitrate Reductase - genetics, Nitrate Reductase - metabolism, Nitric oxide, Nitric Oxide - metabolism, Nitrites, Nitrites - therapeutic use, Oxidation-Reduction, Oxides, Oxygen, P values, Physiological regulation, Proteins, Reactive Oxygen Species - metabolism, Respiration, Rodents, Signal transduction, Ventricular Dysfunction, Left - metabolism