Nitrite as regulator of hypoxic signaling in mammalian physiology.
In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.
van Faassen
Ernst E
EE
Department of Interface Physics, Debye Institute, Utrecht University, Princetonplein 1, 3508 TA Utrecht, The Netherlands. faassen@phys.uu.nl
Bahrami
Soheyl
S
Feelisch
Martin
M
Hogg
Neil
N
Kelm
Malte
M
Kim-Shapiro
Daniel B
DB
Kozlov
Andrey V
AV
Li
Haitao
H
Lundberg
Jon O
JO
Mason
Ron
R
Nohl
Hans
H
Rassaf
Tienush
T
Samouilov
Alexandre
A
Slama-Schwok
Anny
A
Shiva
Sruti
S
Vanin
Anatoly F
AF
Weitzberg
Eddie
E
Zweier
Jay
J
Gladwin
Mark T
MT
D000818:Animals; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D009566:Nitrates / Q000097:blood / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000097:blood / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction; D014664:Vasodilation / Q000502:physiology
D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen