Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivation of glycogen synthase kinase-3beta (GSK3beta) by S(9) phosphorylation is implicated in mechanisms of neuronal survival. Phosphorylation of a distinct site, Y(216), on GSK3beta is necessary for its activity; however, whether this site can be regulated in cells is unknown. Therefore we examined the regulation of Y(216) phosphorylation on GSK3beta in models of neurodegeneration. Nerve growth factor withdrawal from differentiated PC12 cells and staurosporine treatment of SH-SY5Y cells led to increased phosphorylation at Y(216), GSK3beta activity, and cell death. Lithium and insulin, agents that lead to inhibition of GSK3beta and adenoviral-mediated transduction of dominant negative GSK3beta constructs, prevented cell death by the proapoptotic stimuli. Inhibitors induced S(9) phosphorylation and inactivation of GSK3beta but did not affect Y(216) phosphorylation, suggesting that S(9) phosphorylation is sufficient to override GSK3beta activation by Y(216) phosphorylation. Under the conditions examined, increased Y(216) phosphorylation on GSK3beta was not an autophosphorylation response. In resting cells, Y(216) phosphorylation was restricted to GSK3beta present at focal adhesion sites. However, after staurosporine, a dramatic alteration in the immunolocalization pattern was observed, and Y(216)-phosphorylated GSK3beta selectively increased within the nucleus. In rats, Y(216) phosphorylation was increased in degenerating cortical neurons induced by ischemia. Taken together, these results suggest that Y(216) phosphorylation of GSK3beta represents an important mechanism by which cellular insults can lead to neuronal death.
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PMID:Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. 1099 69

Ischemia is a common stress to human brain and is difficult to cure in older individuals. To examine the differences of the response to cerebral ischemia between young and old rat brains, distributions of glycogen synthase kinase-3beta (GSK3beta) and tau proteins were analyzed after 90 min of transient middle cerebral artery occlusion (MCAO) in young (10-11 weeks) and old (15 months) rats by immunohistochemical analyses. At 4 h of reperfusion, strong cytoplasmic and nuclear immunoreactivity for GSK3beta was induced in neurons of lamina I, II, V and VI of the cerebral cortex and dorsal caudate in young brains, while the induction was not observed in lamina I and II of old cerebral cortex. The staining in lamina V and VI and dorsal caudate then gradually decreased until seven days of reperfusion in both animal groups. The staining of tau protein and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) did not show any positive signals in the control brain, but showed positive signals after ischemia with a peak at 24 h and 3 days, respectively. No significant difference was observed in the temporal and spatial patterns of tau and TUNEL stainings between these two groups. These data suggest that GSK3beta may have a role in ischemic neuronal cell death, and that the different spatial expression of GSK3beta between young and old rat brains may partly explain the vulnerability of older neurons after ischemia.
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PMID:Different expression of glycogen synthase kinase-3beta between young and old rat brains after transient middle cerebral artery occlusion. 1154 26

We previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. In perfused rat hearts, PC (4 cycles of 5 minutes of ischemia and 5 minutes of reflow) increased phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3beta, we examined whether PC-induced phosphorylation and inhibition of GSK-3beta is important in PC by using two inhibitors of GSK-3beta, lithium and SB 216763. Pretreatment of perfused rat hearts with lithium or SB 216763, before ischemia, mimicked the protective effects of PC; hearts treated with either lithium or SB 216763 had improved postischemic function and reduced infarct size. These findings indicate that inhibition of GSK-3beta is protective and that this PI3-kinase--dependent signaling pathway may play an important role in ischemic preconditioning.
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PMID:Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. 1188 65

Molecular mechanisms of cardioprotection afforded by modified mexiletine compounds were investigated during ischemia-reperfusion (IR) in Langendorff perfused hearts. Rat hearts were subjected to a global 25 min ischemia followed by reperfusion, either untreated or treated with mexiletine, or three substituted mexiletine derivates (5 muM). A modified mexiletine derivative (H-2693) promoted best the recovery of myocardial energy metabolism (assessed by (31)P NMR spectroscopy) compared to untreated and mexiletine-treated hearts. H-2693 also preserved cardiac contractile function and attenuated the IR-induced lipid peroxidation (TBARS formation) and protein oxidation (carbonyl content). Western blot revealed that H-2693 propagated the phosphorylation of Akt (activation) and its downstream substrate glycogen synthase kinase-3beta (GSK-3beta, inactivation) compared to untreated IR. Parallel treatment with the phosphatidylinositol-3-kinase (upstream activator of Akt) inhibitor wortmannin (100 nM) abolished the beneficial effects of H-2693 on energetics and function, and reduced Akt and GSK-3beta phosphorylation. As a result of the antiapoptotic impacts of Akt activation, H-2693 decreased caspase-3 activity, which was neutralized by wortmannin. Here we first demonstrated that a free radical-entrapping compound could activate the prosurvival Akt pathway beyond its proven ability to scavenge reactive oxygen species. In conclusion, the favorable influence of H-2693 on signaling events during IR may have considerably contributed to its cardioprotective effect.
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PMID:Akt activation induced by an antioxidant compound during ischemia-reperfusion. 1457 8

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart. The effects of AM on GSK-3beta and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3beta but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
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PMID:Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. 1466 48

In a rat model of myocardial ischemic infarction, sodium orthovanadate rescued cells from ischemia/reperfusion injuries. Rats underwent 30 min of myocardial ischemia by occluding the left coronary artery followed by 24 h of reperfusion. Post-treatment with orthovanadate reduced infarct size in a dose-dependent manner. Orthovanadate treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. The cytoprotective action of orthovanadate treatment was closely associated with inhibition of fodrin breakdown. Since orthovanadate is a potent inhibitor for protein tyrosine phosphatases, thereby activating tyrosine kinases and phosphatidylinositol 3-kinase (PI3K) pathways, we investigated activities of protein kinase B (Akt), a downstream target of PI3K in cardiomyocytes. Orthovanadate-induced cytoprotection was associated with partial restoration of reduced Akt activity following myocardial infarction. Restoration of Akt activity by orthovanadate treatment correlated positively with increased phosphorylation of glycogen synthase kinase-3beta and Bad in cardiomyocytes. Furthermore, orthovanadate treatment inhibited caspase-3 activation induced by ischemia. Taken together, orthovanadate post-treatment rescued cardiomyocytes from ischemia/reperfusion injuries via Akt activation and inhibition of fodrin breakdown, thereby inhibiting apoptosis.
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PMID:Cytoprotective effect of sodium orthovanadate on ischemia/reperfusion-induced injury in the rat heart involves Akt activation and inhibition of fodrin breakdown and apoptosis. 1529 57

Ischemia / reperfusion (I / R) injury is related to tissue graft energy status. Insulin, which is currently used in the University of Wisconsin (UW) preservation solution with insulin (UWI), is an anabolic hormone and was shown to exacerbate the hepatic I / R injury in our previous study. In this study, the energy status and regulation of metabolism genes by insulin were investigated in liver grafts preserved by UW solution. Insulin could significantly decrease adenosine triphosphate (ATP) level after 3 hours of preservation, as well as total adenine nucleotides (TANs) and energy charge (EC) levels. Energy regeneration deteriorated in the grafts preserved by insulin in terms of ATP and EC levels at 24 hours after transplantation. The insulin signal was transduced through the insulin receptor substrate-2 (IRS-2) pathway and the activity of IRS-2 was decreased gradually at the messenger ribonucleic acid (mRNA) level during cold preservation. Downstream targeting genes such as sterol regulatory element-binding protein-1c (SREBP-1c), glucokinase (GKC), and fatty acid synthase (FAS) genes, as well as phospho-glycogen synthase kinase-3beta (GSK-3beta) were activated and they showed the similar expression profiles during cold preservation. Lipoprotein metabolism was accelerated by insulin through upregulation of the activity of apolipoprotein C-III (Apo C-III) during cold preservation. The insulin-like growth factor-binding protein-1 pathway was inhibited during cold preservation. In conclusion, insulin in UW solution exacerbates hepatic I / R injury by energy depletion as the graft maintains its anabolic activity. The key enzyme activities of the energy-consuming process of glycogen and fatty acid synthesis as well as lipoprotein metabolism were accelerated by insulin through the IRS-2 / SREBP-1c pathway.
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PMID:Insulin in UW solution exacerbates hepatic ischemia / reperfusion injury by energy depletion through the IRS-2 / SREBP-1c pathway. 1535 11

The mechanism responsible for the enhanced myocardial susceptibility to ischemic insult in patients with type 2 diabetes is not clear. The present study examines the effect of rosiglitazone treatment on cardiac insulin sensitization and its association with cardioprotection from ischemia/reperfusion injury in an animal model of diabetes. Male Zucker diabetic fatty (ZDF) rats were treated with rosiglitazone (3 mg . kg(-1) . day(-1) orally) or vehicle for 8 days before undergoing 30 min of coronary artery ligation, followed by reperfusion for 4 h (apoptosis) or 24 h (infarction). Rosiglitazone reduced the blood levels of glucose, triglycerides, and free fatty acids; enhanced cardiac glucose oxidation; and increased Akt phosphorylation (Akt-pS473) 2.1-fold and Akt kinase activity 1.8-fold in the ischemic myocardium. The phosphorylation of two downstream targets of Akt, glycogen synthase kinase-3beta and FKHR (forkhead transcription factor), was also enhanced by 2- and 2.9-fold, respectively. In rosiglitazone-treated rats, the number of apoptotic cardiomyocytes and the myocardial infarct size were decreased by 58 and 46%, respectively, and the myocardial contractile dysfunction was improved. Blockade of the insulin-Akt signaling pathway by wortmannin in the 8-day rosiglitazone-treated ZDF rats resulted in a markedly diminished cardioprotective effect of rosiglitazone. In addition, 8-day rosiglitazone treatment in Zucker lean rats or 2-day rosiglitazone treatment in ZDF rats, both of which showed no change in whole-body insulin sensitivity, resulted in a significant reduction in cardiac infarct size, but to a lesser degree when compared with that observed in 8-day rosiglitazone-treated ZDF rats. These results suggest that chronic treatment with rosiglitazone protects the heart against ischemia/reperfusion injury in ZDF rats, and that the enhanced cardiac protection observed after rosiglitazone treatment might be attributable in part to an improvement in cardiac insulin sensitivity.
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PMID:Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. 1567 15

Adrenomedullin (AM) has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of delayed AM gene transfer in cerebral ischemia. Three days after a 1-hr occlusion of the middle cerebral artery (MCAO), rats were injected intravenously with adenovirus harboring human AM cDNA. The experiment was terminated 7 days after MCAO. AM gene transfer significantly reduced cerebral infarct size compared with that of rats before virus injection and compared with that of rats injected with control virus. The expression of recombinant human AM was identified in ischemic brain by immunostaining. Morphological analyses showed that AM gene transfer enhanced the survival and migration of astrocytes into the ischemic core. Cerebral ischemia markedly increased astrocyte apoptosis, and AM gene delivery significantly reduced apoptosis to near normal levels as seen in sham control rats. Similarly, in primary cultured astrocytes, AM stimulated cell migration and inhibited hypoxia/reoxygenation-induced apoptosis. The effects of AM on both migration and apoptosis were abolished by calcitonin gene-related peptide [CGRP(8-37)], an AM receptor antagonist. Enhanced cell survival after AM gene transfer was accompanied by markedly increased cerebral nitric oxide and Bcl-2 levels, as well as Akt and GSK-3beta phosphorylation, but reduced NADPH oxidase activity and superoxide production. Inactivation of GSK-3beta by phosphorylation led to reduced GSK-3beta activity and caspase- 3 activation. These results indicate that exogenous AM provides neuroprotection against cerebral ischemia injury by enhancing astrocyte survival and migration and inhibiting apoptosis through suppression of oxidative stress-mediated signaling events.
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PMID:Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. 1568

Here we investigated the neuroprotective effect of 17beta-estradiol in an in vitro model of ischemia. We used organotypic hippocampal slice cultures, acute or chronically treated with 17beta-estradiol (10 nM), and exposed to oxygen and glucose deprivation (OGD). Cellular death was quantified by measuring uptake of propidium iodide (PI), a marker of dead cells. In OGD exposed cultures, treated only with vehicle, about 70% of the CA1 area of hippocampus was labeled with PI, indicating a great percentage of cellular death. When cultures were treated with 17beta-estradiol (acute or chronically), this cellular death was reduced to 15%. This effect was prevented by LY294002 but was not by PD98059. Immunoblotting revealed that both, chronic and acute, treatments with 17beta-estradiol induced the phosphorylation/activation of Akt and the phosphorylation/inactivation of GSK-3beta. Our results show a clear neuroprotective effect of 17beta-estradiol and suggest that this effect could involve PI3-K pathway.
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PMID:Estradiol protects against oxygen and glucose deprivation in rat hippocampal organotypic cultures and activates Akt and inactivates GSK-3beta. 1589 22


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