Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia

Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Journal of Thoracic and Cardiovascular Surgery (Impact Factor: 4.17). 06/2004; 127(5):1262-9. DOI: 10.1016/j.jtcvs.2003.11.032
Source: PubMed


Myocardial injury and dysfunction following ischemia are mediated in part by reactive oxygen species. Pyruvate, a key glycolytic intermediary, is an effective free radical scavenger but unfortunately is limited by aqueous instability. The ester derivative, ethyl pyruvate, is stable in solution and should function as an antioxidant and energy precursor. This study sought to evaluate ethyl pyruvate as a myocardial protective agent in a rat model of ischemia-reperfusion injury.
Rats underwent 30-minute ischemia and 30-minute reperfusion of the left anterior descending coronary artery territory. Immediately prior to both ischemia and reperfusion, animals received an intravenous bolus of either ethyl pyruvate (n = 26) or vehicle control (n = 26). Myocardial high-energy phosphate levels were determined by adenosine triphosphate assay, oxidative injury was measured by lipid peroxidation assay, infarct size was quantified by triphenyltetrazolium chloride staining, and cardiac function was assessed in vivo.
Ethyl pyruvate administration significantly increased myocardial adenosine triphosphate levels compared with control (87.6 +/- 29.2 nmol/g vs 10.0 +/- 2.4 nmol/g, P =.03). In ischemic myocardium, ethyl pyruvate reduced oxidative injury compared with control (63.8 +/- 3.3 nmol/g vs 89.5 +/- 3.0 nmol/g, P <.001). Ethyl pyruvate diminished infarct size as a percentage of area at risk (25.3% +/- 1.5% vs 33.6% +/- 2.1%, P =.005). Ethyl pyruvate improved myocardial function compared with control (maximum pressure: 86.6 +/- 2.9 mm Hg vs 73.5 +/- 2.5 mm Hg, P <.001; maximum rate of pressure rise: 3518 +/- 243 mm Hg/s vs 2703 +/- 175 mm Hg/s, P =.005; maximal rate of ventricular systolic volume ejection: 3097 +/- 479 microL/s vs 2120 +/- 287 microL/s, P =.04; ejection fraction: 41.9% +/- 3.8% vs 31.4% +/- 4.1%, P =.03; cardiac output: 26.7 +/- 0.9 mL/min vs 22.7 +/- 1.3 mL/min, P =.01; and end-systolic pressure-volume relationship slope: 1.09 +/- 0.22 vs 0.59 +/- 0.2, P =.02).
In this study of myocardial ischemia-reperfusion injury, ethyl pyruvate enhanced myocardial adenosine triphosphate levels, attenuated myocardial oxidative injury, decreased infarct size, and preserved cardiac function.

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    • "Ethyl pyruvate (EP), a stable lipophilic ester derivative of pyruvate, is currently known as a therapeutic agent. It also functions as an antioxidant (Woo et al. 2004). EP is currently used as a food additive and its use in food is classified as generally recognized as safe by US Food and Drug Administration. "
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    ABSTRACT: Vaporized ethyl pyruvate (EP) was evaluated for its efficiency for decontamination of parsley from Escherichia coli O157:H7 and Staphylococcus aureus. Inoculated parsleys (∼104 or ∼106 cfu/g) were treated with 0 (control sample), 100, 400 and 1,000 μL of vaporized EP in 2.6-L closed-lid food containers. Samples were evaluated for bacterial growth and visual acceptance during treatment. In the case of decontamination of E. coli O157:H7, 1,000 μL EP treatments completely inhibited the bacterial population and enabled 100% growth inhibition levels (GILs) in both inoculum levels. In low inoculation of S. aureus, the difference between the counts of the control and 1,000 μL EP-treated samples was higher than 2 logs after the storage. In high inoculum, 400 or 1,000 μL EP-treated parsleys had significantly (P < 0.05) lower S. aureus populations as compared with the control sample. EP treatment retarded parsley decay; however, it caused some yellowness on the parsley leaves.Practical ApplicationsSafety of minimally processed fruits and vegetables is of great concern worldwide as no decontamination treatment is included in their processing. Different methods such as washing with chemical sanitizers, pulsed ultraviolet light, high pressure and ionized radiation have been tested for decontamination of fresh products. In general, these methods achieve less than a 2-log reduction and negatively affect organoleptical properties of the products. Surface structure of the product also influences the effectiveness of surface decontamination processes as pathogens may penetrate into protected sites within plant tissue. Vaporized ethyl pyruvate (EP) has potential to remove these disadvantages because of its volatility which enables it to reach the pathogens that are hidden within plant structures. In this study, EP was effective against both Escherichia coli O157:H7 and Staphylococcus aureus on fresh parsley. As a conclusion, EP was confirmed as an effective agent for decontamination of parsleys and as a successful alternative for other decontamination methods.
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    • "Both the antagonist or the recombinant protein had no effect on RACE KO mice, which suggest that HMGB1 signaling through RAGE inhibits the reparative response after MI. Also, administration of ethyl pyruvate, which inhibits the release of HMGB1, preserves cardiac function after extended myocardial ischemia followed by reperfusion [103]. Interestingly, preconditioning with HMGB1 shows protection against ischemia-reperfusion injury [104]. "
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    ABSTRACT: During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research.
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    • "Ethyl pyruvate (EP) is a simple aliphatic ester of pyruvic acid and has been shown to confer protective effects in various disease models. For example, EP administration improved survival in mice with established lethal sepsis and systemic inflammation and diminished ischemia-induced myocardial injury [1] [2]. EP also significantly reduced infarct volumes in the postischemic brain [3] and attenuated kainic acid-induced neuronal cell death in the CA1 and CA3 regions of the mouse hippocampus [4]. "
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    ABSTRACT: Ethyl pyruvate (EP) has been shown to have anti-inflammatory effects and confer protective effects in various pathological conditions. For example, EP inhibits secretion of high mobility group box 1 (HMGB1), which is known to be released from activated or dying cells and aggravate inflammatory pathways. In the present study, we investigated whether EP reduces HMGB1 phosphorylation and release in ischemic brain and in cultured microglia. In the postischemic brains (60min middle cerebral artery occlusion (MCAO)), HMGB1 was released extracellularly, generating dual peaks in cerebrospinal fluid (CSF) around 1 and 7 days after ischemic insult, which were probably generated from damaged neurons and activated inflammatory cells, respectively. We showed that treatment with EP 30min post-MCAO (5mg/kg, i.v.), which has been shown to confer a robust neuroprotective effect in the postischemic brain, reduced both peaks. In addition, delayed EP treatment from 4 days post-MCAO reduced HMGB1accumulation in CSF at 7 day post-MCAO in the absence of accompanying amelioration of ischemic brain damage, indicating that the suppression of HMGB1 release is a direct effect. We also found that EP markedly suppressed the LPS-induced nuclear translocations of protein kinase C alpha and calcium/calmodulin-dependent protein kinase IV, HMGB1 phosphorylation, and subsequent secretion of HMGB1 induced by LPS in BV2 cells and EP-mediated above-mentioned effects were also independent of cell death or survival. These results indicate that EP inhibits HMGB1 phosphorylation and release in activated microglia, which might be responsible for EP-mediated suppression of HMGB1 release in the postischemic brain.
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