Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass

Ryou, Myoung Gwi; Flaherty, Devin C.; Hoxha, Besim; Sun, Jie; Gurji, Hunaid; Rodriguez, Steven; Bell, Glenn D.; Olivencia‐Yurvati, Albert H.; Mallet, Robert T.

doi:10.1152/ajpheart.01213.2008

Cited by 20 publications

(26 citation statements)

References 43 publications

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“…162 Here, pyruvate-enriched cardioplegia stabilized HIF-1α content, which paralleled robust myocardial mRNA expression and synthesis of EPO. Elements of EPO’s intracellular signaling cascades, Erk and eNOS, were activated following pyruvate cardioplegia.…”

Section: Induction Of Erythropoietin and Neuroprotection By Pyruvatementioning

confidence: 82%

Erythropoietin: Powerful protection of ischemic and post-ischemic brain

Nguyen

Cherry

Scott

et al. 2014

Exp Biol Med (Maywood)

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Ischemic brain injury inflicted by stroke and cardiac arrest ranks among the leading causes of death and long-term disability in the United States. The brain consumes large amounts of metabolic substrates and oxygen to sustain its energy requirements. Consequently, the brain is exquisitely sensitive to interruptions in its blood supply, and suffers irreversible damage after 10–15 minutes of severe ischemia. Effective treatments to protect the brain from stroke and cardiac arrest have proven elusive, due to the complexities of the injury cascades ignited by ischemia and reperfusion. Although recombinant tissue plasminogen activator and therapeutic hypothermia have proven efficacious for stroke and cardiac arrest, respectively, these treatments are constrained by narrow therapeutic windows, potentially detrimental side effects and the limited availability of hypothermia equipment. Mounting evidence demonstrates the cytokine hormone erythropoietin (EPO) to be a powerful neuroprotective agent and a potential adjuvant to established therapies. Classically, EPO originating primarily in the kidneys promotes erythrocyte production by suppressing apoptosis of proerythroid progenitors in bone marrow. However, the brain is capable of producing EPO, and EPO’s membrane receptors and signaling components also are expressed in neurons and astrocytes. EPO activates signaling cascades that increase the brain’s resistance to ischemia-reperfusion stress by stabilizing mitochondrial membranes, limiting formation of reactive oxygen and nitrogen intermediates, and suppressing pro-inflammatory cytokine production and neutrophil infiltration. Collectively, these mechanisms preserve functional brain tissue and, thus, improve neurocognitive recovery from brain ischemia. This article reviews the mechanisms mediating EPO-induced brain protection, critiques the clinical utility of exogenous EPO to preserve brain threatened by ischemic stroke and cardiac arrest, and discusses the prospects for induction of EPO production within the brain by the intermediary metabolite, pyruvate.

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Section: Induction Of Erythropoietin and Neuroprotection By Pyruvatementioning

confidence: 82%

Erythropoietin: Powerful protection of ischemic and post-ischemic brain

Nguyen

Cherry

Scott

et al. 2014

Exp Biol Med (Maywood)

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“…The role of HIF in cell survival from I/R injury has been widely reported 14,15,21,41 . MB significantly increases HIF-1α protein content compared to both normoxic and OGD control groups (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Ryou¹,

Choudhury²,

Li³

et al. 2015

Neuroscience

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Brain ischemia and reperfusion (I/R) injury occurs in various pathological conditions, but there is no effective treatment currently available in clinical practice. Methylene blue (MB) is a century old drug with a newly discovered protective function in the ischemic stroke model. In the current investigation we studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia inducible factor-1α (HIF-1α) in an in vitro oxygen and glucose deprivation (OGD)-reoxygenation model. Methods HT22 cells were exposed to OGD (0.1% O2, 6h) and reoxygenation (21% O2, 24h). Cell viability was determined with the calcein AM assay. The dynamic change of intracellular O2 concentration was monitored by fluorescence lifetime imaging microscopy (FLTIM). Glucose uptake was quantified using the 2-[N-(7-Nitrobenz-2-Oxa- 1,3-Diazol-4-yl)Amino]- 2-Deoxy-D-Glucose (2-NBDG) assay. ATP concentration and glycolytic enzyme activity were examined by spectrophotometry. Protein content changes were measured by immunoblot: HIF-1α, prolyl hydroxylase 2(PHD2), erythropoietin (EPO), Akt, mTOR, and PIP5K. The contribution of HIF-1α activation in the MB-induced neuroprotective mechanism was confirmed by blocking HIF-1α activation with 2-methoxyestradiol-2 (2-MeOE2) and by transiently transfecting constitutively active HIF-1α. Results MB increases cell viability by about 50% vs. OGD control. Compared to the corresponding control, MB increases intracellular O2 concentration and glucose uptake as well as the activities of hexokinase and G-6-PDH, and ATP concentration. MB activates the EPO signaling pathway with a corresponding increase in HIF-1α. Phosphorylation of Akt was significantly increased with MB treatment followed by activation of the mTOR pathway. Importantly, we observed, MB increased nuclear translocation of HIF-1α vs. control (about 3 folds), which was shown by a ratio of nuclear:cytoplasmic HIF-1α protein content. Conclusion We conclude that MB protects the hippocampus derived neuronal cells against OGD-reoxygenation injury by enhancing energy metabolism and increasing HIF-1α protein content accompanied by an activation of the EPO signaling pathway.

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“…Furthermore, pyruvate can indirectly contribute to ROS detoxification by inducing synthesis of erythropoietin, a cytokine with antioxidant properties (Toba et al, 2012). We reported that pyruvate increases HIF-1-driven mRNA expression and protein content of erythropoietin by stabilizing the O 2 -regulated HIF-1α (Ryou et al, 2009, 2012). In accordance with pyruvate’s antioxidant properties, the current study demonstrated that pyruvate enhanced NADPH/NADP + redox state, suppressed ROS generation after OGD and reoxygenation, and maintained the integrity of vascular endothelial tight junctions.…”

Section: Discussionmentioning

confidence: 96%

Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation

et al. 2013

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Clinical application of recombinant tissue plasminogen activator (rtPA) for stroke is limited by hemorrhagic transformation, which narrows rtPA’s therapeutic window. In addition, mounting evidence indicates that rtPA is potentially neurotoxic if it traverses a compromised blood brain barrier. Here, we demonstrated that pyruvate protects cultured HT22 neuronal and primary microvascular endothelial cells co-cultured with primary astrocytes from oxygen glucose deprivation (OGD)/reoxygenation stress and rtPA cytotoxicity. After 3 or 6 h OGD, cells were reoxygenated with 11 mmol/L glucose±pyruvate (8 mmol/L) and/or rtPA (10 μg/ml). Measured variables included cellular viability (calcein AM and annexin-V/propidium iodide), reactive oxygen species (ROS; mitosox red and 2′,7′-dichlorofluorescein diacetate), NADPH, NADP+ and ATP contents (spectrophotometry), matrix metalloproteinase-2 (MMP2) activities (gelatin zymography), and cellular contents of MMP2, tissue inhibitor of metalloproteinase-2 (TIMP2), and phosphor-activation of anti-apoptotic p70s6 kinase, Akt and Erk (immunoblot). Pyruvate prevented the loss of HT22 cells after 3 h OGD±rtPA. After 6 h OGD, rtPA sharply lowered cell viability; pyruvate dampened this effect. Three hours OGD and 4 h reoxygenation with rtPA increased ROS formation by about 50%. Pyruvate prevented this ROS formation and doubled cellular NADPH/NADP+ ratio and ATP content. In endothelial cell monolayers, 3 h OGD and 24 h reoxygenation increased FITC-dextran leakage, indicating disruption of intercellular junctions. Although rtPA exacerbated this effect, pyruvate prevented it while sharply lowering MMP2/TIMP2 ratio and increasing phosphorylation of p70s6 kinase, Akt and Erk. Pyruvate protects neuronal cells and microvascular endothelium from hypoxia-reoxygenation and cytotoxic action of rtPA while reducing ROS and activating anti-apoptotic signaling. These results support the proposed use of pyruvate as an adjuvant to dampen the side effects of rtPA treatment, thereby extending rtPA’s therapeutic window.

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Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass

Cited by 20 publications

References 43 publications

Erythropoietin: Powerful protection of ischemic and post-ischemic brain

Erythropoietin: Powerful protection of ischemic and post-ischemic brain

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation

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