Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury.

Abstract

The nitrite anion is reduced to nitric oxide (NO*) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO* 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* 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* generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO* 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 [corrected]

• Authors: Ulrike B Hendgen-Cotta, Marc W Merx, Sruti Shiva, Joel Schmitz, Stefanie Becher, Johann P Klare, Heinz-Jürgen Steinhoff, Axel Goedecke, Jürgen Schrader, Mark T Gladwin, Malte Kelm, Tienush Rassaf
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 29 Pg. 10256-61 (Jul 22 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18632562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myoglobin
• Nitrites
• Reactive Oxygen Species
• Nitric Oxide
• Heme
• Nitrate Reductase
• Aconitate Hydratase

Topics

• Aconitate Hydratase (antagonists & inhibitors)
• Animals
• Cell Respiration (physiology)
• Cell Survival (physiology)
• Heme (metabolism)
• In Vitro Techniques
• Male
• Mice
• Mice, Knockout
• Mitochondria, Heart (metabolism)
• Myocardial Infarction (prevention & control)
• Myocardial Reperfusion Injury (drug therapy, genetics, metabolism, pathology)
• Myocardium (metabolism, pathology)
• Myoglobin (deficiency, genetics, metabolism)
• Nitrate Reductase (deficiency, genetics, metabolism)
• Nitric Oxide (metabolism)
• Nitrites (therapeutic use)
• Oxidation-Reduction
• Reactive Oxygen Species (metabolism)
• Ventricular Dysfunction, Left (metabolism)