Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury.
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]
Hendgen-Cotta
Ulrike B
UB
Department of Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
Merx
Marc W
MW
Shiva
Sruti
S
Schmitz
Joel
J
Becher
Stefanie
S
Klare
Johann P
JP
Steinhoff
Heinz-Jürgen
HJ
Goedecke
Axel
A
Schrader
Jürgen
J
Gladwin
Mark T
MT
Kelm
Malte
M
Rassaf
Tienush
T
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors; D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006418:Heme / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009203:Myocardial Infarction / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009211:Myoglobin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050901:Nitrate Reductase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000627:therapeutic use; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
D009211:Myoglobin; D009573:Nitrites; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006418:Heme; D050901:Nitrate Reductase; D000154:Aconitate Hydratase