Increased O-linked β-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats

Nöt, László G.; Brocks, Charlye A; Vámhidy, L; Marchase, Richard B.; Chatham, John C.

doi:10.1097/ccm.0b013e3181cb10b3

Cited by 41 publications

(27 citation statements)

References 39 publications

(69 reference statements)

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“…Finally, myeloperoxidase (MPO), a marker used for neutrophil activation in post-THS animals (12, 17, 40), is not limited to the neutrophil but is also bound to the vascular endothelium and released by heparin into circulation (63). These examples do not negate the fact that THS clearly has a systemic impact since gut injury, inflammation, gender differences and organ injury are seen in models not using heparin (52,64,65) and slightly reduce endothelial cell viability in our RL resuscitation (Fig. 1E) model in the absence of any anticoagulants.…”

Section: Discussionmentioning

confidence: 78%

Heparin Use in a Rat Hemorrhagic Shock Model Induces Biologic Activity in Mesenteric Lymph Separate from Shock

Qin

Prescott²,

Deitch³

et al. 2011

Shock

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Experimental data has shown that mesenteric lymph from rats subjected to trauma-hemorrhagic shock (THS) but not trauma-sham shock (TSS) induces neutrophil activation, cytotoxicity, decreased red blood cell deformability and bone marrow colony growth suppression. These data have lead to the hypothesis that gut factors produced from THS enter the systemic circulation via the mesenteric lymphatics and contribute to the progression of Multiple Organ Failure (MOF) following THS. Ongoing studies designed to identify bioactive lymph agents implicated factors associated with the heparin use in the THS procedure. We investigated if heparin itself was responsible for reported toxicity to human umbilical vein endothelial cells (HUVECs). HUVEC toxicity was not induced by lymph when alternate anti-coagulants (citrate and EDTA) were used in THS. HUVEC toxicity was induced by lymph after heparin but not saline or citrate injection into TSS and naïve animals and was dose dependent. Activities of both heparin-releasable lipases (lipoprotein (LPL) and hepatic (HL)) were detected in the plasma and lymph from THS and naïve animals receiving heparin but not citrate or saline. Lymph-induced HUVEC toxicity correlated with lymph lipase activities. Finally, incubation of HUVECs with purified LPL added to naïve lymph induced toxicity in vitro. These data show that heparin, not THS, is responsible for the reported lymph-mediated HUVEC toxicity through its release of lipases into the lymph. These findings can provide alternative explanations for several of the THS effects reported in the literature using heparin models thus necessitating a review of previous work in this field.

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Section: Discussionmentioning

confidence: 78%

Heparin Use in a Rat Hemorrhagic Shock Model Induces Biologic Activity in Mesenteric Lymph Separate from Shock

Qin

Prescott²,

Deitch³

et al. 2011

Shock

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“…23,[36][37][38][39] PDFs contain different stressors with the potential to induce the CSR, such as hyperosmolar concentrations of glucose, GDP, and acidic lactate. Whereas GDP and acidic lactate are associated with acute adverse effects of PDF, only high glucose was necessary to induce O-GlcNAc.…”

Section: Discussionmentioning

confidence: 99%

Dynamic O-Linked N-Acetylglucosamine Modification of Proteins Affects Stress Responses and Survival of Mesothelial Cells Exposed to Peritoneal Dialysis Fluids

Bender

Vychytil

Bialas

et al. 2014

Journal of the American Society of Nephrology

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The ability of cells to respond and survive stressful conditions is determined, in part, by the attachment of O-linked N-acetylglucosamine (O-GlcNAc) to proteins (O-GlcNAcylation), a post-translational modification dependent on glucose and glutamine. This study investigates the role of dynamic O-GlcNAcylation of mesothelial cell proteins in cell survival during exposure to glucose-based peritoneal dialysis fluid (PDF). Immortalized human mesothelial cells and primary mesothelial cells, cultured from human omentum or clinical effluent of PD patients, were assessed for O-GlcNAcylation under normal conditions or after exposure to PDF. The dynamic status of O-GlcNAcylation and effects on cellular survival were investigated by chemical modulation with 6-diazo-5-oxo-L-norleucine (DON) to decrease or O-(2-acetamido-2-deoxy-Dglucopyranosylidene)amino N-phenyl carbamate (PUGNAc) to increase O-GlcNAc levels. Viability was decreased by reducing O-GlcNAc levels by DON, which also led to suppressed expression of the cytoprotective heat shock protein 72. In contrast, increasing O-GlcNAc levels by PUGNAc or alanyl-glutamine led to significantly improved cell survival paralleled by higher heat shock protein 72 levels during PDF treatment. Addition of alanyl-glutamine increased O-GlcNAcylation and partly counteracted its inhibition by DON, also leading to improved cell survival. Immunofluorescent analysis of clinical samples showed that the O-GlcNAc signal primarily originates from mesothelial cells. In conclusion, this study identified O-GlcNAcylation in mesothelial cells as a potentially important molecular mechanism after exposure to PDF. Modulating O-GlcNAc levels by clinically feasible interventions might evolve as a novel therapeutic target for the preservation of peritoneal membrane integrity in PD.

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“…O-GlcNAc levels are dynamically elevated in response to many forms of cellular stress (13,14), including oxidative stress (13,14) and ischemia reperfusion (I/R) injury (14 -19). Elevating O-GlcNAc levels prior to (13-18, 20 -26) or immediately after (27)(28)(29)(30)(31) injury significantly improves survival. In contrast, decreasing O-GlcNAc levels sensitizes cells and tissues to apoptosis and necrosis (13, 18, 24 -26).…”

mentioning

confidence: 99%

Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress

Groves

Maduka

O’Meally

et al. 2017

Journal of Biological Chemistry

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The dynamic post-translational modification linked β--acetylglucosamine (-GlcNAc) regulates thousands of nuclear, cytoplasmic, and mitochondrial proteins. Cellular stress, including oxidative stress, results in increased GlcNAcylation of numerous proteins, and this increase is thought to promote cell survival. The mechanisms by which theGlcNAc transferase (OGT) and the GlcNAcase (OGA), the enzymes that add and removeGlcNAc, respectively, are regulated during oxidative stress to alter GlcNAcylation are not fully characterized. Here, we demonstrate that oxidative stress leads to elevatedGlcNAc levels in U2OS cells but has little impact on the activity of OGT. In contrast, the expression and activity of OGA are enhanced. We hypothesized that this seeming paradox could be explained by proteins that bind to and control the local activity or substrate targeting of OGA, thereby resulting in the observed stress-induced elevations of GlcNAc. To identify potential protein partners, we utilized BioID proximity biotinylation in combination withtable sotopicabeling of mino acids inell culture (SILAC). This analysis revealed 90 OGA-interacting partners, many of which exhibited increased binding to OGA upon stress. The associations of OGA with fatty acid synthase (FAS), filamin-A, heat shock cognate 70-kDa protein, and OGT were confirmed by co-immunoprecipitation. The pool of OGA bound to FAS demonstrated a substantial (∼85%) reduction in specific activity, suggesting that FAS inhibits OGA. Consistent with this observation, FAS overexpression augmented stress-induced GlcNAcylation. Although the mechanism by which FAS sequesters OGA remains unknown, these data suggest that FAS fine-tunes the cell's response to stress and injury by remodeling cellularGlcNAcylation.

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Increased O-linked β-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats

Cited by 41 publications

References 39 publications

Heparin Use in a Rat Hemorrhagic Shock Model Induces Biologic Activity in Mesenteric Lymph Separate from Shock

Heparin Use in a Rat Hemorrhagic Shock Model Induces Biologic Activity in Mesenteric Lymph Separate from Shock

Dynamic O-Linked N-Acetylglucosamine Modification of Proteins Affects Stress Responses and Survival of Mesothelial Cells Exposed to Peritoneal Dialysis Fluids

Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress

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