TY - JOUR
T1 - Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis
AU - Shiva, Sruti
AU - Wang, Xunde
AU - Ringwood, Lorna A.
AU - Xu, Xueying
AU - Yuditskaya, Susan
AU - Annavajjhala, Vidhya
AU - Miyajima, Hiroaki
AU - Hogg, Neil
AU - Harris, Zena Leah
AU - Gladwin, Mark T.
PY - 2006/9
Y1 - 2006/9
N2 - Nitrite represents a bioactive reservoir of nitric oxide (NO) that may modulate vasodilation, respiration and cytoprotection after ischemia-reperfusion injury. Although nitrite formation is thought to occur via reaction of NO with oxygen, this third-order reaction cannot compete kinetically with the reaction of NO with hemoglobin to form nitrate. Indeed, the formation of nitrite from NO in the blood is limited when plasma is substituted with physiological buffers, which suggests that plasma contains metal-based enzymatic pathways for nitrite synthesis. We therefore hypothesized that the multicopper oxidase, ceruloplasmin, could oxidize NO to NO+, with subsequent hydration to nitrite. Accordingly, plasma NO oxidase activity was decreased after ceruloplasmin immunodepletion, in ceruloplasmin knockout mice and in people with congenital aceruloplasminemia. Compared to controls, plasma nitrite concentrations were substantially reduced in ceruloplasmin knockout mice, which were more susceptible to liver infarction after ischemia and reperfusion. The extent of hepatocellular infarction normalized after nitrite repletion. These data suggest new functions for the multicopper oxidases in endocrine NO homeostasis and nitrite synthesis, and they support the hypothesis that physiological concentrations of nitrite contribute to hypoxic signaling and cytoprotection.
AB - Nitrite represents a bioactive reservoir of nitric oxide (NO) that may modulate vasodilation, respiration and cytoprotection after ischemia-reperfusion injury. Although nitrite formation is thought to occur via reaction of NO with oxygen, this third-order reaction cannot compete kinetically with the reaction of NO with hemoglobin to form nitrate. Indeed, the formation of nitrite from NO in the blood is limited when plasma is substituted with physiological buffers, which suggests that plasma contains metal-based enzymatic pathways for nitrite synthesis. We therefore hypothesized that the multicopper oxidase, ceruloplasmin, could oxidize NO to NO+, with subsequent hydration to nitrite. Accordingly, plasma NO oxidase activity was decreased after ceruloplasmin immunodepletion, in ceruloplasmin knockout mice and in people with congenital aceruloplasminemia. Compared to controls, plasma nitrite concentrations were substantially reduced in ceruloplasmin knockout mice, which were more susceptible to liver infarction after ischemia and reperfusion. The extent of hepatocellular infarction normalized after nitrite repletion. These data suggest new functions for the multicopper oxidases in endocrine NO homeostasis and nitrite synthesis, and they support the hypothesis that physiological concentrations of nitrite contribute to hypoxic signaling and cytoprotection.
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U2 - 10.1038/nchembio813
DO - 10.1038/nchembio813
M3 - Article
C2 - 16906150
AN - SCOPUS:33747602092
SN - 1552-4450
VL - 2
SP - 486
EP - 493
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -