Shock:
April 2008 - Volume 29 - Issue 4 - pp 431-440
doi: 10.1097/SHK.0b013e3181598bad
Review Article
Hexosamine Biosynthesis and Protein O-Glycosylation: the First Line of Defense Against Stress, Ischemia, and Trauma
Chatham, John C.; Nöt, Laszlo G.; Fülöp, Norbert; Marchase, Richard B.
 Author Information
*Department of Medicine, Division of Cardiovascular Disease; and †Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama
Received 8 Jun 2007; first review completed 28 Jun 2007; accepted in final form 15 Aug 2007
Address reprint requests to John C. Chatham, Department of Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South, MCLM 684, Birmingham, AL 35294-0005. E-mail: jchatham@uab.edu.
This work was supported in part by the National Institutes of Health (grant nos. HL067464 and HL079364 to J.C.C. and HL076175 to R.B.M.).
Abstract
An early and rapid response to severe injury or trauma is the development of hyperglycemia, which has long been thought to be an essential survival response by providing fuel for vital organ systems and facilitating mobilization of interstitial fluid reserves by increasing osmolarity. However, glucose can also be metabolized via the hexosamine biosynthesis pathway (HBP), leading to the synthesis of uridine diphosphate N-acetyl-glucosamine (UDP-GlcNAc). UDP-GlcNAc is a substrate for the addition, via an O-linkage, of a single N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins (O-glycosylation, O-GlcNAc). There is increasing appreciation that protein O-glycosylation is a highly dynamic posttranslational modification that plays a key role in signal transduction pathways. Sustained increases in O-GlcNAc have been implicated in the development of diabetes and diabetic complications; however, recent studies have demonstrated that stress leads to a transient increase in O-GlcNAc levels that is associated with increased tolerance to stress. Indeed, activation of pathways leading to O-GlcNAc formation improves cell survival after I/R injury, whereas inhibition of O-GlcNAc formation decreases cell survival. In addition, in rodent models of trauma-hemorrhage, increasing O-GlcNAc levels during resuscitation improves cardiac function and organ perfusion and attenuates the inflammatory response. At the cellular level, increasing O-GlcNAc levels attenuates nuclear factor-κB activation. It is noteworthy that other metabolic-based treatments for severe injury such as glucose-insulin-potassium and glutamine also lead to increased HBP flux and O-GlcNAc levels. The goal of this review is to summarize our current understanding of the role of the HBP and O-GlcNAc on the regulation of cell function and survival and to present evidence to support the notion that activation of these pathways represents a novel treatment strategy for severe injury and trauma.
INTRODUCTION
It is well appreciated that cells and organisms have evolved mechanisms that sense stressful conditions and respond to these sensors with adaptations that afford them a higher probability of surviving (1). The focus of this review is to explore the concept that one of these adaptations, engaged before transcription/translation, involves the channeling of glucose units from oxidative metabolism into the hexosamine biosynthesis pathway (HBP) to be used for the glycosylation of nuclear and cytoplasmic proteins.
Interestingly, this channeling of glucose at the cellular level is amplified by one of the best described of the "fight or flight" responses at the organismal level, the stress hormone-induced induction of hyperglycemia (2, 3). Although hyperglycemia has been reported to be an independent risk factor for adverse outcomes after severe injury (2, 4-6), a number of experimental studies have demonstrated that inhibition of the hyperglycemic response to trauma decreased survival (7-10). Traditionally, stress-induced hyperglycemia was thought to be an essential survival response because it provided fuel for vital organ systems and/or facilitated mobilization of interstitial fluid reserves by increasing osmolarity (2, 3, 7, 11-15). However, in addition to being metabolized via energy-producing pathways such as glycolysis, glucose is also metabolized by the HBP (Fig. 1), resulting in the synthesis of uridine diphosphate N-acetyl-glucosamine (UDP-GlcNAc). One fate of UDP-GlcNAc is as a substrate for the addition, via an O-linkage, of a single N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of both nuclear and cytoplasmic proteins (Fig. 1).
Sustained increases in HBP flux and protein O-GlcNAc levels have been implicated in the development of diabetes and diabetic complications; however, recent studies have demonstrated that stress leads to an acute and transient increase in O-GlcNAc levels that is associated with increased tolerance to stress (16, 17). Indeed, activation of pathways leading to O-GlcNAc formation improves cell survival after I/R injury, whereas inhibition of O-GlcNAc formation decreases cell survival (16, 17). Several hundred proteins have now been identified as being subject to O-GlcNAc modification, and a comprehensive list of these proteins can be found in the following publications (18-22). A substantial number of proteins that are targets for O-GlcNAc are also involved in mediating cellular stress responses, and these are listed in Table 1. Studies have also demonstrated that at the cellular level increasing O-GlcNAc levels alters the response of several key signaling pathways to stress, including nuclear factor (NF)-κB (29) and mitogen-activated protein kinase (MAPK) pathways (43, 44; Table 1). In rodent models of trauma-hemorrhage, increasing O-GlcNAc levels during resuscitation improves cardiac function and organ perfusion and attenuates the inflammatory response (57, 58). It is noteworthy that other metabolic-based treatments for severe injury such as glucose-insulin-potassium (GIK) and glutamine also lead to increased HBP flux and O-GlcNAc levels (16, 59).
The goal of this review is to summarize our current understanding of the role of the HBP and O-GlcNAc on the regulation of cell function and survival and to present evidence to support our hypothesis that stress-induced hyperglycemia favors survival because it is coupled to increased formation of protein O-GlcNAc. We begin with a brief discussion of cellular stress responses and follow with an overview of the HBP and O-GlcNAc; the reader is also referred to several excellent reviews on the latter topic that provide much more detailed information than can be covered here (18-20, 60-63). Subsequently, we discuss the role of the HBP and O-GlcNAc in regulating cell survival and demonstrate how the beneficial effects of other metabolic-based therapies for trauma, namely, GIK and glutamine, may also be mediated via the HBP and O-GlcNAc.
THE HEXOSAMINE BIOSYNTHESIS PATHWAY AND PROTEIN O-GLYCOSYLATION
At the cellular level, stress is sensed primarily by two pathways: one involves damage to macromolecules, and the other changes in cellular redox potential, including an increase in reactive oxygen species (ROS) (1). Reactive oxygen species alters protein function through mechanisms, often involving susceptible cysteine residues (64); within the glucose metabolic pathway, the activity of glyceraldehyde 3-phosphate dehydrogenase is particularly sensitive to inhibition by ROS, and, consequently, it has been proposed to play a pivotal role as a sensor of intracellular oxidative stress (65). Glyceraldehyde 3-phosphate dehydrogenase serves as a control point for the entry of glucose into glycolysis and oxidative phosphorylation; thus, its inhibition results in glucose units being channeled into other pathways, including the pentose phosphate shunt and, of particular interest to this review, the HBP, which, we propose, has profound ramifications to various aspects of cell survival.
It has been estimated that under normal conditions, the HBP consumes 2% to 5% of the glucose taken up by cells (66) (it should be noted that this widely cited figure is an estimate based on cultured adipocytes, and a direct measure of glucose flux through this pathway has yet to be determined either in isolated perfused organs or in tissues in vivo). The key regulatory enzyme of the pathway is L-glutamine-D-fructose 6-phosphate amidotransferase (GFAT), which converts fructose 6-phosphate to glucosamine 6-phosphate with glutamine as the amine donor (67; Fig. 1). Thus, flux through GFAT is glutamine dependent and can be inhibited by the glutamine analogs 6-diazo-5-oxo-L-norleucine and O-diazoacetyl-L-serine (azaserine) (68). UDP-GlcNAc is the primary end-product of the HBP and is a substrate for multiple glycosylation reactions catalyzed by various GlcNAc transferases, including a unique O-GlcNAc transferase (OGT; uridine diphospho-N-acetylglucosamine: polypeptide β-N-acetylglucosaminyltransferase) (69, 70; Fig. 1). O-N-Acetyl-glucosamine transferase is distinct from all other protein glycosyltransferases because it is not found in the secretory pathway but rather in the nucleocytoplasmic compartment, where it catalyzes the formation of a reversible posttranslational protein modification involving the attachment of GlcNAc via an O-linkage to specific serine and threonine residues on numerous nuclear and cytoplasmic proteins (71, 72). It is noteworthy that OGT is highly conserved across species; for example, Caenorhabditis elegans OGT shows 68% identity to the human form at the amino acid sequence level (73), and that OGT gene deletion was embryonically lethal (74), demonstrating that OGT activity/O-glycosylation is vital for life.
Although regulation of OGT activity is complex and not fully understood, its activity is very sensitive to changes in concentration of UDP-GlcNAc (75). Thus, a stress-induced increase in HBP flux will lead to an increase in UDP-GlcNAc levels, which in turn will increase the flux through OGT, leading to the elevation of O-GlcNAc levels on nuclear and cytoplasmic proteins (44). In addition to levels of UDP-GlcNAc and OGT activity, the level of O-GlcNAc on nucleocytoplasmic proteins is also regulated by N-acetylglucosaminidase (O-GlcNAcase), which catalyzes the removal of the sugar moiety from the proteins (19, 62). O-GlcNAcase activity and protein are localized primarily in the cytosol (90%), with the remaining 10% found in the nucleus (76). An analog of GlcNAc, O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) has been shown to be an effective and relatively specific inhibitor of O-GlcNAcase (77). The dynamic nature of O-GlcNAc formation is evident by the fact that cellular levels of O-GlcNAc are increased rapidly by inhibiting O-GlcNAcase with PUGNAc (16, 37).
To date, several hundred different proteins are known to be modified by O-GlcNAc, including transcription factors, kinases, phosphatases, cytoskeletal proteins, nuclear hormone receptors, nuclear pore proteins, signal transduction molecules, and actin regulatory proteins (18, 19), many of which are known to play a role in mediating cellular stress responses (Table 1). On some proteins such as eNOS (54), estrogen receptor β (78), C-terminal domain of RNA polymerase II (79), and c-myc (80), residues that act as acceptor sites for O-GlcNAc are also the same as the sites of phosphorylation; however, there can also be multiple and distinct phosphorylation/O-glycosylation sites on the same protein. Thus, alterations in glycosylation can have direct effects on multiple phosphorylation cascades; indeed, increased HBP flux and O-GlcNAcylation have been implicated in altering the activation of a number of critical regulatory kinase pathways, including NF-κB, p38 MAPK, Akt, and protein kinase C (PKC) (52, 54, 81, 82, 83). However, in contrast to the hundreds of kinases and phosphatases catalyzing phosphorylation (84), there is only one gene encoding OGT (44) and a single gene encoding the complementary O-GlcNAcase (85). This suggests to us that this system may in some manner act as a "master switch," catalyzing a posttranscriptional modification on multiple proteins with a common goal.
PROTEIN O-GLYCOSYLATION AND INCREASED TOLERANCE TO STRESS
Most of the available literature regarding the role of O-GlcNAc in regulating cellular function have been in the context of various disease states such as insulin resistance and the adverse effects of diabetes (23, 31, 32, 34, 37, 54, 86-91) and the development of cancer (80, 92) and neurodegenerative disorders such as Alzheimer disease (19, 93, 94). However, in contrast to these adverse effects, Zachara et al. (17) showed that in mammalian cells, stress stimuli increased protein O-GlcNAc levels, and augmentation of this response increased tolerance to the same stress stimuli. In contrast, they found that inhibition of O-GlcNAc formation increased the sensitivity to stress (17). Others have reported that inhibition of GFAT decreased O-GlcNAc levels and reduced cell survival after heat stress (95). Manzari et al. (96) reported that hypoxic stress increased GFAT expression in murine macrophages. In isolated cardiomyocytes, I/R resulted in a transient increase in O-GlcNAc levels that was dependent on exogenous glucose (16). Furthermore, augmentation of this response by the addition of glucosamine or increased glucose levels significantly improved cell survival, whereas attenuation of the response either by removing glucose or inhibiting OGT reduced survival (16). In the intact heart, ischemia increased both UDP-GlcNAc and O-GlcNAc levels (44), and perfusion with glucosamine significantly increased cardiac O-GlcNAc levels, improved cardiac function, and decreased tissue injury after reperfusion (44, 97).
A number of mechanisms have been proposed to account for the protection associated with increased O-GlcNAc levels such as increased synthesis of heat shock protein (HSP)40 and HSP70 (17), both of which are also known to be subject to O-GlcNAc modification. The activity of the transcription factor Sp1 also increases when modified by O-GlcNAc (42, 98), and this may contribute to the increased synthesis of HSPs (99) and prosurvival Bcl-2 family members (100). However, Sohn et al. (95) found that O-GlcNAc-mediated protection was not dependent on changes in HSP110, HSP90, HSP70, or HSP27 expression levels. Furthermore, we demonstrated that isolated heart protection against either calcium overload or I/R injury was conferred after a brief (5-15 min) pretreatment with glucosamine (Fig. 2) (97), suggesting that de novo protein synthesis is not required for protection. Indeed, our initial studies in cultured cells (16, 101-104) and the isolated heart (97, 105) demonstrated that activation of the HBP led to a decrease in calcium influx brought about by various stimuli, including I/R (16). One consequence of minimizing cytoplasmic calcium levels is to prevent activation of the protease calpain, and we have recently demonstrated that glucosamine and PUGNAc, both of which by independent mechanisms increase O-GlcNAc levels, also attenuated the I/R-induced increase in calpain-mediated proteolysis (106). Thus, one mechanism of protection associated with increased O-GlcNAc levels can be attenuation of the calcium overload that often accompanies stresses such as I/R (107, 108).
In isolated cardiomyocytes, elevated O-GlcNAc levels decreased apoptosis resulting from I/R (16) and attenuated the loss of mitochondrial membrane potential induced by acute oxidative stress (50). The Bcl-2 protein family, which include both proapoptotic and antiapoptotic factors, have been implicated in the regulation of mitochondrially mediated apoptosis (109). We found that increasing O-GlcNAc formation was associated with increased mitochondrial levels of the prosurvival Bcl-2 (50), which can contribute to the increased tolerance to apoptosis. We have also demonstrated that in the isolated heart, increasing O-GlcNAc levels with glucosamine attenuated the ischemia-induced increase in p38 MAPK phosphorylation (44). An increase in O-GlcNAc has also been reported to inhibit protein degradation (20). For example, O-GlcNAc modification prolongs the half-life of eukaryotic initiation factor 2α-p67, Sp1, and estrogen receptor (ER) β. Increased O-GlcNAc may also block phosphorylation sites that promote protein degradation (20). A reduction in O-GlcNAc on Sp1 has been associated with more rapid degradation, suggesting that O-GlcNAc alters the targeting of Sp1 to the proteasome (110). In addition, many proteins that make up the proteasome complex are targets for O-GlcNAc modification (55, 111), and an increase in O-GlcNAc decreased proteasome activity (55). Although proteasome inhibition has been reported to both decrease (112, 113) and exacerbate ischemic injury (114), this does not preclude the possibility that short-term inhibition of proteasome function can contribute to the protection associated with an increase in O-GlcNAc levels.
Thus, increased formation of O-GlcNAc may confer short-term protection via transcriptionally independent mechanisms such as attenuation of calcium-mediated stress responses, reduced protein degradation, cellular redistribution of prosurvival factors such as Bcl-2, or modulation of stress-activated kinase pathways. In addition, longer-term protection may also be facilitated via increased transcription of prosurvival factors such as HSPs.
STRESS-INDUCED HYPERGLYCEMIA
Severe injury such as surgical trauma, hemorrhage, shock, sepsis, and burns typically result in a hypermetabolic state that occurs as a result of increased gluconeogenesis and glycogen degradation in response to stress hormones such as glucagon, cortisol, and epinephrine (2, 3). These responses are accompanied by hyperinsulinemia, but the rapid development of insulin resistance (2, 3, 115) slows uptake and accumulation of glucose by muscle and adipocytes and prevents insulin-mediated suppression of gluconeogenesis (2, 3, 116). Together, this series of events leads to a prolongation of the hyperglycemic state (2, 3), which has long been thought to be an essential survival response because it provided fuel for vital organ systems and/or facilitated mobilization of interstitial fluid reserves by increasing osmolarity (2, 7, 11-15). A number of studies have reported that starvation prevents stress-induced hyperglycemia, and that this is associated with decreased survival after hemorrhagic shock (7-10). Furthermore, administration of glucose after starvation significantly improved survival. (7-10); however, it should be noted that glucose administration to animals after starvation did not lead to marked hyperglycemia; rather, it resulted in serum glucose levels similar to those seen in fed animals subjected to trauma (i.e., ∼10 - 11 mM) (10). These studies demonstrated that the ability to mount an acute hyperglycemic response to hemorrhage is a critical factor for survival. As noted above, Du et al. (42) reported that hyperglycemia-induced ROS production inhibited glyceraldehyde 3-phosphate dehydrogenase activity, decreasing glycolytic flux, thereby increasing flux through the HBP and increasing UDP-GlcNAc levels. Thus, the acute hypermetabolic state that arises in response to stress not only provides additional substrate for the HBP but also potentially inhibits other pathways of glucose metabolism. This further increases the availability of glucose for O-GlcNAc synthesis, thereby potentially conferring protection as described above.
Contrary to the notion that stress-induced hyperglycemia is a key survival factor, recent studies have suggested that hyperglycemia is an independent risk factor for adverse outcomes in a number of critical illnesses, including trauma (2), and that preventing hyperglycemia with intensive insulin therapy significantly improves outcomes (4-6). This may seem to contradict the experimental studies demonstrating that stress-induced hyperglycemia favors survival. However, it is important to note that the experimental studies were performed in otherwise normal healthy animals with no underlying metabolic disease. Moreover, it is our contention that protection is mediated via a specific cellular response to stress (namely, the synthesis of protein O-GlcNAc) that is independent from other sequelae such as oxidative stress, which may, even in the short term, be deleterious.
This hypothesis is not inconsistent with data demonstrating that intensive insulin therapy for critically ill patients improves outcomes because insulin-stimulated glucose uptake is known to activate pathways leading to the formation of O-GlcNAc. Furthermore, the beneficial effects of a transient hyperglycemic response to stress does not preclude the deleterious consequences of persistent hyperglycemia, which may reflect underlying metabolic diseases such as glucose intolerance or insulin resistance that are becoming increasingly prevalent. This is supported by the observation that in patients with acute myocardial infarction, fasting glucose levels the day after admission are a better predictor of early mortality than glucose levels at the time of admission (117, 118). The failure of elevated glucose levels to fall within 24 h of admission is also associated with increased mortality in nondiabetic patients with myocardial infarction (119). These data further support our contention that the adverse effects of hyperglycemia in the setting of trauma are a consequence of sustained or persistent hyperglycemia, possibly as a consequence of underlying metabolic dysfunction, and not related to the transient hyperglycemic response induced by the initial injury that we proposed is beneficial.
METABOLIC INTERVENTIONS IN THE TREATMENT OF STRESS AND TRAUMA
Despite the reported averse effects of chronic hyperglycemia discussed above (4), there is a literature dating from the 1960s (120) surrounding the effectiveness of acute GIK treatment in protecting against injury after a range of insults, including hypovolemic shock (121), burn trauma (122), septic shock (123), cardiac surgery (124, 125), and myocardial infarction (126). Glucose-insulin-potassium has been most widely used in the setting of cardiac surgery and myocardial infarction. In the latter, it has been reported to reduce relative mortality by approximately 30% (126), which is greater than more widely used treatments such as aspirin, thrombolytics, and angiotensin-converting enzyme inhibitors (127-129). More recently, GIK therapy has been shown to improve outcomes when used during cardiac bypass surgery (130, 131). Glucose-insulin-potassium also improved hemodynamic profiles in pressor-resistant hypodynamic septic shock (123). Interestingly, hyperinsulinemia/euglycemia therapy has also been shown to be beneficial in the treatment of β-blocker and calcium channel antagonist toxicity (132-136). However, despite repeated studies showing benefit in a number of different pathological settings, GIK therapy has not gained widespread use due at least in part to the disparate results of the various studies and because there has been little consensus as to potential mechanisms of action (125, 137).
Glutamine has also been shown to be protective in a number of settings, including ischemic injury (138, 139) and trauma (140, 141). For example, Singleton and Wischmeyer (142) reported that glutamine administration increases the expression of HSP70 in gut epithelial cells and was protective against oxidant and heat injury. Glutamine treatment also successfully reduced TNF-α and IL-1β expression and led to an improved survival rate after endotoxemia. The authors also demonstrated that glutamine treatment prevented the activation of NF-κB and stress kinase pathways (143). Furthermore, glutamine also prevented the development of acute respiratory distress syndrome after cecal ligation and puncture-induced sepsis in rodents (143). A number of mechanisms have been postulated for the protection associated with glutamine treatment, including increased energy production (138, 139), attenuation of NF-κB activation (143), and increased HSP70 expression (144).
Both hyperglycemia and glutamine have been shown to increase flux through the HBP and to increase UDP-GlcNAc levels (145); thus, a common feature of two of the most widely studied metabolic therapies for treatment of trauma is that they both have the potential to increase the synthesis of O-GlcNAc. In support of this, we have demonstrated at the cellular level that hyperglycemia-mediated protection against I/R injury was dependent on flux through the HBP and associated with increased O-GlcNAc levels (16). We have also recently shown in the intact heart that glutamine-induced ischemic protection was dependent on flux through GFAT and the subsequent increase in O-GlcNAc (146). It is also noteworthy that the protection associated with both glutamine and O-GlcNAc have been linked to increased HSP70 expression (17, 142) and attenuation of stress-induced inflammatory responses (143).
O-GlcNAc AND TRAUMA-HEMORRHAGE
Yang et al. (26) demonstrated that administration of glucosamine during resuscitation after trauma-hemorrhage improved cardiac output 2-fold compared with vehicle-treated controls. They also found that glucosamine treatment improved perfusion of various organ systems, including the kidney and brain, and attenuated the trauma-hemorrhage-induced increase in serum levels of the inflammatory cytokines IL-6 and TNF-α. In vivo administration of glucosamine also increased O-GlcNAc protein levels in multiple tissues, supporting the notion that enhanced O-GlcNAc levels on nucleocytoplasmic proteins mediated the protection. However, in addition to increasing O-GlcNAc levels, glucosamine also increases glucosamine-6-phosphate levels and can potentially be metabolized to fructose-6-phosphate, thereby increasing glycolytic flux. Thus, the protection associated with glucosamine treatment can be mediated via a number of other pathways. As noted above, inhibition of O-GlcNAcase, which is responsible for the removal of O-GlcNAc from proteins, has been shown to rapidly increase O-GlcNAc levels in cell culture studies (37), and the O-GlcNAcase inhibitor PUGNAc had protective effects similar to glucosamine in both neonatal rat ventricular myocytes and the perfused heart (16, 106). Therefore, we also examined whether PUGNAc administration after trauma-hemorrhage improved recovery of organ perfusion and function. We found that intravenous administration of PUGNAc midway during resuscitation significantly improved cardiac output (Fig. 3), decreased total peripheral resistance, and increased perfusion of critical organs systems compared with vehicle-treated controls (58). Similar to glucosamine, PUGNAc also attenuated the increase in plasma IL-6 and TNF-α levels and significantly increased O-GlcNAc levels in the heart, liver, and kidney (Fig. 3).
Glucosamine treatment has also been shown to increase short-term survival after trauma-hemorrhage without resuscitation (147). Recent studies also suggest that PUGNAc improved 24-h survival rates after trauma hemorrhage and resuscitation, which was also associated with decreased inflammatory cytokines and reduced liver injury (Nöt et al., unpublished data). The similar effects of glucosamine and PUGNAc support the notion that the protection associated with both interventions is mediated via increased protein O-GlcNAc levels.
INFLAMMATION AND O-GlcNAc MODIFICATION
Glucosamine sulfate is a popular nutritional supplement that is used as a treatment of osteoarthritis; however, oral administration of the accepted oral dose (1,500 mg) yielded a maximum serum concentration of approximately 12 μM (148), which is well less than the range we have found to yield a cytoprotective effect. Nevertheless, a number of studies have demonstrated that glucosamine may have anti-inflammatory effects. For example, Ma et al. (149) demonstrated that glucosamine suppressed the activation of T lymphoblasts and dendritic in a dose-dependent manner, and Shikhman et al. (150) found that both glucosamine and N-acetyl-glucosamine inhibited IL-1β- and TNF-α-induced NO production in normal human chondrocytes. Kneass and Marchase (151) also reported that O-GlcNAc modification plays an important role in rapid and dynamic neutrophil signal transduction especially with respect to chemotaxis. Glucosamine has also been reported to down-regulate TNF-α- and IFN-γ-induced intracellular adhesion molecule 1 expression (30), which seemed to be mediated by preventing nuclear translocation of NF-κB subunit p65. The p65 subunit of NF-κB has been shown to be subject to O-GlcNAc modification (28).
As discussed above, increasing O-GlcNAc levels with either glucosamine or PUGNAc attenuated the trauma-hemorrhage-induced increase in inflammatory cytokines (57, 58). Thus, part of the protection associated with elevated O-GlcNAc levels can be mediated via an anti-inflammatory effect, possibly due to attenuation of NF-κB signaling. We found that glucosamine treatment during resuscitation significantly attenuated the trauma-hemorrhage-induced increase in intracellular adhesion molecule 1 expression, IκB-α phosphorylation, NF-κB expression, and NF-κB DNA binding activity (29). These results further suggest that attenuation of the NF-κB signaling pathway may contribute to the protection associated with increased protein O-GlcNAc levels.
CONCLUDING REMARKS
In this review, we have summarized data that have led us to propose that enhancing the activation of the HBP that normally occurs with stress will benefit organs and organisms subjected to ischemia or hemorrhage. Although studies to date have been carried out primarily in rats or isolated rat cells and organs, the effectiveness of GIK in humans is consistent with the possibility of translating this proposal to clinical use. The efficacy of increasing O-GlcNAc in organs to be transplanted as well as after ischemia or trauma in human subjects has yet to be determined. Nevertheless, intravenous administration of glucosamine, at concentrations in the range we have shown to be therapeutically effective, was well tolerated in normal healthy volunteers (152, 153). Thus, the application of strategies for increasing O-GlcNAc in the context of ischemia or trauma remains a promising alternative to current therapeutic regimens.
However, the demonstration of a definitive cause-and-effect relationship between increased O-GlcNAc synthesis and increased tolerance to stress at the organismal level may be challenging given that OGT gene deletion is embryonically lethal (74, 154). Nevertheless, studies at the cellular level using adenoviral and siRNA techniques to increase and reduce OGT levels, respectively, support the notion that flux through OGT plays a critical role in mediating the response to stress (50). Considerable work also remains to understand the mechanisms by which up-regulation of O-GlcNAc leads to cellular protection. A particular challenge relates to how O-GlcNAc modification of specific proteins is regulated. In contrast to the many kinases and phosphatases that contribute specificity to the addition and removal of phosphate, there is only one gene encoding OGT and one gene encoding O-GlcNAc transferase. Thus, the development of small molecule kinase inhibitors, which have provided the attractive targets for development of novel therapeutics, would seem to be an unlikely approach for modulating O-GlcNAc levels on specific proteins.
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Keyword Highlighting
Highlight selected keywords in the article text.
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