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PMID: 18632562 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 29 ·2008-07-22 ·Pages 10256-61

Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, Steinhoff HJ, Goedecke A, Schrader J, Gladwin MT, Kelm M, Rassaf T

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]

MeSH Terms
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
Chemicals
Myoglobin Nitrites Reactive Oxygen Species Nitric Oxide Heme Nitrate Reductase Aconitate Hydratase
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Hendgen-Cotta Ulrike B
Department of Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
Merx Marc W
Shiva Sruti
Schmitz Joel
Becher Stefanie
Klare Johann P
Steinhoff Heinz-Jürgen
Goedecke Axel
Schrader Jürgen
Gladwin Mark T
Kelm Malte
Rassaf Tienush
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0801336105
Published
2008-07-22
Epub
2008-00-16
Pages
10256-61
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2481313
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1073/pnas.0801336105 PMC Full Text View journal details
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