Pyruvate enhances recovery of rat hearts after ischemia and reperfusion by preventing free radical generation

DeBoer, Laurence W.V.; Bekx, P. A.; Han, Luheng; Steinke, Leah

doi:10.1152/ajpheart.1993.265.5.h1571

Cited by 62 publications

(58 citation statements)

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“…Involvement of PHD inhibition for lactate-induced HIF-1a and HIF-2a stabilization does not exclude additional effects of lactate on the cellular redox status, as lactate oxidation to pyruvate (the lactate dehydrogenase 1 reaction) increases the NADH/NAD C ratio and pyruvate has antioxidant properties. 49,50 Considering that cancer cells chronically adapted to extracellular acidity activate HIF-2a and become addicted to glutamine, 51 the contribution of protons cotransported with lactate by MCT1 certainly deserves further consideration.…”

Section: Discussionmentioning

confidence: 99%

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

et al. 2016

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Oxygenated cancer cells have a high metabolic plasticity as they can use glucose, glutamine and lactate as main substrates to support their bioenergetic and biosynthetic activities. Metabolic optimization requires integration. While glycolysis and glutaminolysis can cooperate to support cellular proliferation, oxidative lactate metabolism opposes glycolysis in oxidative cancer cells engaged in a symbiotic relation with their hypoxic/glycolytic neighbors. However, little is known concerning the relationship between oxidative lactate metabolism and glutamine metabolism. Using SiHa and HeLa human cancer cells, this study reports that intracellular lactate signaling promotes glutamine uptake and metabolism in oxidative cancer cells. It depends on the uptake of extracellular lactate by monocarboxylate transporter 1 (MCT1). Lactate first stabilizes hypoxia-inducible factor-2a (HIF-2a), and HIF-2a then transactivates c-Myc in a pathway that mimics a response to hypoxia. Consequently, lactate-induced c-Myc activation triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in improved glutamine uptake and catabolism. Elucidation of this metabolic dependence could be of therapeutic interest. First, inhibitors of lactate uptake targeting MCT1 are currently entering clinical trials. They have the potential to indirectly repress glutaminolysis. Second, in oxidative cancer cells, resistance to glutaminolysis inhibition could arise from compensation by oxidative lactate metabolism and increased lactate signaling.

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Section: Discussionmentioning

confidence: 99%

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

et al. 2016

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“…In 1991, Salahudeen et al (39) reported that intravenous infusion of sodium pyruvate protects rats from renal parenchymal injury induced by injecting H 2 O 2 into the renal artery. After the publication of that paper, a number of other investigators reported that treatment with pyruvate could protect animals from the deleterious effects of a variety of conditions thought to be mediated by ROS, including myocardial I/R (4,7,8,11,35), intestinal I/R (6), and HS/R (30).…”

Section: Discussionmentioning

confidence: 99%

“…REACTIVE SPECIES OF OXYGEN (ROS) have been implicated as being important mediators in a variety of pathological conditions, including burns (20), various forms of ischemia-reperfusion (I/R) injury (8,15,16,26), and hemorrhagic shock (9,10,17,32 Pyruvate, a key intermediate in cellular metabolism, is an effective scavenger of ROS. In a reaction characteristic of ␣-keto carboxylic acids in general, pyruvic acid (the simplest member of this class of compounds) rapidly undergoes nonenzymatic decarboxylation in the presence of H 2 O 2 to form acetate, carbon dioxide, and water (5,33).…”

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confidence: 99%

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Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock

Yang¹,

Gallo²,

Baust³

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

156

143

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Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-κB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.

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“…In recent years, the effect of various free radical scavengers on PTP opening has been investigated in different models of ischemia/reperfusion. Pyruvate may protect the heart against ischemia/reperfusion due to its free radical scavenging activity although it is also a good fuel for oxidative phosphorylation which, unlike glucose, does not require ATP-dependent activation before oxidation [156,157]. Indeed, in the Langendorff-perfused rat heart it was demonstrated directly that addition of pyruvate to the perfusion medium before the onset of ischemia significantly inhibited PTP opening which was associated with a greater recovery of cardiac function [77].…”

Section: Inhibition Of Ptp Opening By Free Radical Scavengersmentioning

confidence: 99%

Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection

Javadov

Karmazyn²

2007

Cell Physiol Biochem

252

160

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In recent years, mitochondria have been recognized as regulators of cell death via both apoptosis and necrosis in addition to their essential role for cell survival. Cellular dysfunctions induced by intra- or extracellular insults converge on mitochondria and induce a sudden increase in permeability of the inner mitochondrial membrane, the so-called mitochondrial permeability transition. The mitochondrial permeability transition is caused by the opening of permeability transition pores (PTP) in the inner mitochondrial membrane with subsequent loss of ionic homeostasis, matrix swelling and outer membrane rupture. The detailed molecular mechanisms underlying the PTP-induced cellular dysfunction during cardiac pathology such as ischemia/reperfusion or post-infarction remodeling remain to be elucidated. However, a growing body of evidence supports the concept that pharmacological inhibition of the PTP is an effective and promising strategy for the protection of the heart against ischemia/reperfusion injury and for attenuation of the remodeling process which contributes to heart failure. This review summarizes and discusses current data on i) the structure and function of the PTP, ii) possible mechanisms and consequences of PTP opening and iii) the inhibition of PTP opening as a therapeutic approach for treatment of heart disease.

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Pyruvate enhances recovery of rat hearts after ischemia and reperfusion by preventing free radical generation

Cited by 62 publications

References 0 publications

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock

Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection

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