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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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Nitrite mediates both acute and delayed cytoprotection after I/R injury to the heart and liver. (A) Model of hepatic ischemia and myocardial infarction in which nitrite or saline was administered either 24 h before or during ischemia. (B) Plasma ALT levels 5 h into reperfusion in mice after sham surgery, sham surgery with nitrite treatment, ischemia with acute nitrite treatment, or ischemia with nitrite preconditioning (PC). (C) Infarct size as a percentage of area at risk 24 h after myocardial infarction in the absence of nitrite (I/R), with nitrite treatment 5 min before reperfusion (acute), or nitrite treatment 24 h before myocardial infarction (PC). (D) Representative sections of myocardium stained with Evan's blue and triphenyltetrazolium chloride 24 h after infarction in mice receiving no nitrite (I/R + vehicle), acute nitrite treatment, or nitrite preconditioning. *, P < 0.05 in comparison with the I/R + vehicle group; **, P < 0.01 versus the I/R + vehicle group.
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fig1: Nitrite mediates both acute and delayed cytoprotection after I/R injury to the heart and liver. (A) Model of hepatic ischemia and myocardial infarction in which nitrite or saline was administered either 24 h before or during ischemia. (B) Plasma ALT levels 5 h into reperfusion in mice after sham surgery, sham surgery with nitrite treatment, ischemia with acute nitrite treatment, or ischemia with nitrite preconditioning (PC). (C) Infarct size as a percentage of area at risk 24 h after myocardial infarction in the absence of nitrite (I/R), with nitrite treatment 5 min before reperfusion (acute), or nitrite treatment 24 h before myocardial infarction (PC). (D) Representative sections of myocardium stained with Evan's blue and triphenyltetrazolium chloride 24 h after infarction in mice receiving no nitrite (I/R + vehicle), acute nitrite treatment, or nitrite preconditioning. *, P < 0.05 in comparison with the I/R + vehicle group; **, P < 0.01 versus the I/R + vehicle group.

Mentions: Transient nonlethal ischemia, termed the ischemic preconditioning “trigger,” evokes cellular resilience to I/R (32). Importantly, there exist two temporal windows of I/R tolerance: acute, or classical, ischemic preconditioning, lasting minutes to a few hours after the ischemic trigger, and delayed ischemic preconditioning, evident 1–3 d after the transient ischemic trigger. Although nanomole doses of nitrite mediate cytoprotection when administered during ischemia or immediately before reperfusion (8, 9), it is not known whether nitrite can temporally replicate delayed preconditioning. To test this, mice were administered one bolus intraperitoneal injection of nitrite (48 nmol) or saline and subjected to either myocardial infarction or hepatic ischemia 24 h later (Fig. 1 A). After hepatic I/R, serum alanine aminotransferase (ALT) levels, representing hepatic injury, increased (525 ± 40 U/liter) compared with sham surgical controls (50 ± 10 U/liter). Nitrite administered both acutely and 24 h before ischemia attenuated the increase in ALT (210 and 220 ± 30 U/liter, respectively) to a similar degree (Fig. 1 B). Similarly, nitrite administration acutely or 24 h before ischemia significantly reduced myocardial infarct size (18 ± 4 and 35 ± 14%, respectively) compared with saline-treated mice (53 ± 5%; Fig. 1, C and D). Thus nitrite exerts potent cytoprotective effects after I/R injury temporally analogous to ischemic preconditioning.


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)

Nitrite mediates both acute and delayed cytoprotection after I/R injury to the heart and liver. (A) Model of hepatic ischemia and myocardial infarction in which nitrite or saline was administered either 24 h before or during ischemia. (B) Plasma ALT levels 5 h into reperfusion in mice after sham surgery, sham surgery with nitrite treatment, ischemia with acute nitrite treatment, or ischemia with nitrite preconditioning (PC). (C) Infarct size as a percentage of area at risk 24 h after myocardial infarction in the absence of nitrite (I/R), with nitrite treatment 5 min before reperfusion (acute), or nitrite treatment 24 h before myocardial infarction (PC). (D) Representative sections of myocardium stained with Evan's blue and triphenyltetrazolium chloride 24 h after infarction in mice receiving no nitrite (I/R + vehicle), acute nitrite treatment, or nitrite preconditioning. *, P < 0.05 in comparison with the I/R + vehicle group; **, P < 0.01 versus the I/R + vehicle group.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Nitrite mediates both acute and delayed cytoprotection after I/R injury to the heart and liver. (A) Model of hepatic ischemia and myocardial infarction in which nitrite or saline was administered either 24 h before or during ischemia. (B) Plasma ALT levels 5 h into reperfusion in mice after sham surgery, sham surgery with nitrite treatment, ischemia with acute nitrite treatment, or ischemia with nitrite preconditioning (PC). (C) Infarct size as a percentage of area at risk 24 h after myocardial infarction in the absence of nitrite (I/R), with nitrite treatment 5 min before reperfusion (acute), or nitrite treatment 24 h before myocardial infarction (PC). (D) Representative sections of myocardium stained with Evan's blue and triphenyltetrazolium chloride 24 h after infarction in mice receiving no nitrite (I/R + vehicle), acute nitrite treatment, or nitrite preconditioning. *, P < 0.05 in comparison with the I/R + vehicle group; **, P < 0.01 versus the I/R + vehicle group.
Mentions: Transient nonlethal ischemia, termed the ischemic preconditioning “trigger,” evokes cellular resilience to I/R (32). Importantly, there exist two temporal windows of I/R tolerance: acute, or classical, ischemic preconditioning, lasting minutes to a few hours after the ischemic trigger, and delayed ischemic preconditioning, evident 1–3 d after the transient ischemic trigger. Although nanomole doses of nitrite mediate cytoprotection when administered during ischemia or immediately before reperfusion (8, 9), it is not known whether nitrite can temporally replicate delayed preconditioning. To test this, mice were administered one bolus intraperitoneal injection of nitrite (48 nmol) or saline and subjected to either myocardial infarction or hepatic ischemia 24 h later (Fig. 1 A). After hepatic I/R, serum alanine aminotransferase (ALT) levels, representing hepatic injury, increased (525 ± 40 U/liter) compared with sham surgical controls (50 ± 10 U/liter). Nitrite administered both acutely and 24 h before ischemia attenuated the increase in ALT (210 and 220 ± 30 U/liter, respectively) to a similar degree (Fig. 1 B). Similarly, nitrite administration acutely or 24 h before ischemia significantly reduced myocardial infarct size (18 ± 4 and 35 ± 14%, respectively) compared with saline-treated mice (53 ± 5%; Fig. 1, C and D). Thus nitrite exerts potent cytoprotective effects after I/R injury temporally analogous to ischemic preconditioning.

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