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Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer.

Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, Gladwin MT - J. Exp. Med. (2007)

Bottom Line: Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program.This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation.These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet.

View Article: PubMed Central - PubMed

Affiliation: Vascular Medicine Branch, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
Nitrite (NO(2)(-)) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II-IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet.

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Hepatic and myocardial I/R injury are attenuated in mice after oral nitrite therapy. (A) The effects of oral nitrite preconditioning (PC) on the severity of hepatic I/R injury (measured as aspartate aminotransferase [AST] and ALT) in mice. Mice received nitrite via oral gavage at 24 h before 45 min of hepatic ischemia and 5 h of reperfusion. Numbers for each group are shown inside the bars. (B) Bar graph of oral nitrite preconditioning and myocardial I/R injury in mice. Mice received oral nitrite at 24 h before 30 min of ischemia and 24 h of reperfusion. The myocardial area-at-risk (AAR) per total left ventricle (LV) was not significantly different between study groups (NS). The myocardial infarct size (Inf) per area-at-risk was significantly (P < 0.0001) reduced in the oral nitrite preconditioning group when compared with the oral vehicle group. Eight animals were investigated in each group.
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fig8: Hepatic and myocardial I/R injury are attenuated in mice after oral nitrite therapy. (A) The effects of oral nitrite preconditioning (PC) on the severity of hepatic I/R injury (measured as aspartate aminotransferase [AST] and ALT) in mice. Mice received nitrite via oral gavage at 24 h before 45 min of hepatic ischemia and 5 h of reperfusion. Numbers for each group are shown inside the bars. (B) Bar graph of oral nitrite preconditioning and myocardial I/R injury in mice. Mice received oral nitrite at 24 h before 30 min of ischemia and 24 h of reperfusion. The myocardial area-at-risk (AAR) per total left ventricle (LV) was not significantly different between study groups (NS). The myocardial infarct size (Inf) per area-at-risk was significantly (P < 0.0001) reduced in the oral nitrite preconditioning group when compared with the oral vehicle group. Eight animals were investigated in each group.

Mentions: Several chemical agents, including rotenone and amobarbitol, are known to inhibit complex I and confer protection to mitochondria after I/R. However, these agents are not practical therapeutic candidates and certainly are not naturally occurring compounds. Conversely, nitrite forms from the reduction of dietary nitrate by oral bacterial flora and is a potential cardioprotective agent in the nitrate-rich Mediterranean diet (47, 48). To evaluate whether oral nitrite would promote preconditioning cytoprotection after I/R injury, we next tested oral dosing of nitrite. To begin to explore this, nitrite or saline vehicle was administered to mice via oral gavage 24 h before in vivo hepatic or cardiac I/R. Both liver and heart I/R were evaluated 24 h after a single oral gavage of 200 μl of 100 mg/liter sodium nitrite. This would correspond to 9.6 μmol of sodium nitrite per kilogram. Because the total body load of nitrite after ingestion of a nitrate-rich meal (i.e., 100 g of spinach) amounts to >1 μmol/kg (47), our dose is consistent with the daily nitrite intake on the Mediterranean diet. This regimen replicated the cytoprotection evoked by the earlier intraperitoneal administration of nitrite used in the previous experiments performed in this study (Fig. 8, A and B).


Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer.

Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, Gladwin MT - J. Exp. Med. (2007)

Hepatic and myocardial I/R injury are attenuated in mice after oral nitrite therapy. (A) The effects of oral nitrite preconditioning (PC) on the severity of hepatic I/R injury (measured as aspartate aminotransferase [AST] and ALT) in mice. Mice received nitrite via oral gavage at 24 h before 45 min of hepatic ischemia and 5 h of reperfusion. Numbers for each group are shown inside the bars. (B) Bar graph of oral nitrite preconditioning and myocardial I/R injury in mice. Mice received oral nitrite at 24 h before 30 min of ischemia and 24 h of reperfusion. The myocardial area-at-risk (AAR) per total left ventricle (LV) was not significantly different between study groups (NS). The myocardial infarct size (Inf) per area-at-risk was significantly (P < 0.0001) reduced in the oral nitrite preconditioning group when compared with the oral vehicle group. Eight animals were investigated in each group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118713&req=5

fig8: Hepatic and myocardial I/R injury are attenuated in mice after oral nitrite therapy. (A) The effects of oral nitrite preconditioning (PC) on the severity of hepatic I/R injury (measured as aspartate aminotransferase [AST] and ALT) in mice. Mice received nitrite via oral gavage at 24 h before 45 min of hepatic ischemia and 5 h of reperfusion. Numbers for each group are shown inside the bars. (B) Bar graph of oral nitrite preconditioning and myocardial I/R injury in mice. Mice received oral nitrite at 24 h before 30 min of ischemia and 24 h of reperfusion. The myocardial area-at-risk (AAR) per total left ventricle (LV) was not significantly different between study groups (NS). The myocardial infarct size (Inf) per area-at-risk was significantly (P < 0.0001) reduced in the oral nitrite preconditioning group when compared with the oral vehicle group. Eight animals were investigated in each group.
Mentions: Several chemical agents, including rotenone and amobarbitol, are known to inhibit complex I and confer protection to mitochondria after I/R. However, these agents are not practical therapeutic candidates and certainly are not naturally occurring compounds. Conversely, nitrite forms from the reduction of dietary nitrate by oral bacterial flora and is a potential cardioprotective agent in the nitrate-rich Mediterranean diet (47, 48). To evaluate whether oral nitrite would promote preconditioning cytoprotection after I/R injury, we next tested oral dosing of nitrite. To begin to explore this, nitrite or saline vehicle was administered to mice via oral gavage 24 h before in vivo hepatic or cardiac I/R. Both liver and heart I/R were evaluated 24 h after a single oral gavage of 200 μl of 100 mg/liter sodium nitrite. This would correspond to 9.6 μmol of sodium nitrite per kilogram. Because the total body load of nitrite after ingestion of a nitrate-rich meal (i.e., 100 g of spinach) amounts to >1 μmol/kg (47), our dose is consistent with the daily nitrite intake on the Mediterranean diet. This regimen replicated the cytoprotection evoked by the earlier intraperitoneal administration of nitrite used in the previous experiments performed in this study (Fig. 8, A and B).

Bottom Line: Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program.This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation.These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet.

View Article: PubMed Central - PubMed

Affiliation: Vascular Medicine Branch, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
Nitrite (NO(2)(-)) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II-IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet.

Show MeSH
Related in: MedlinePlus