Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inactivation of glycogen synthase kinase-3beta (GSK-3beta) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3beta (Ser9) and the highly homologous GSK-3alpha (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.
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PMID:Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse. 1858 16

Repetitive cycles of reflow/reocclusion in the initial 2 min following release of a prolonged coronary occlusion, i.e., ischemic postconditioning (IPoC), salvages ischemic myocardium. We have proposed that the intermittent ischemia prevents formation of mitochondrial permeability transition pores (MPTP) by maintaining an acidic myocardial pH for several minutes until survival kinases can be activated. To determine other requisites of IPoC, isolated rabbit hearts were subjected to 30 min of regional myocardial ischemia and 120 min of reperfusion. Infarct size was determined by staining with triphenyltetrazolium chloride. During the first 2 min of reperfusion the perfusate was either at pH 7.4 following equilibration with 95% O(2)/5% CO(2), pH 6.9 following equilibration with 80% N(2)/20% CO(2), or pH 7.8 following equilibration with 100% O(2). Whereas acidic, oxygenated perfusate for the first 2 min of reperfusion was cardioprotective, protection was lost when acidic perfusate was hypoxic. However, the acidic, hypoxic hearts could be rescued by addition of phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, to the perfusate. Therefore, both low pH and restoration of oxygenation are necessary for protection, and the signaling step requiring combined oxygen and H(+) must be upstream of PKC. To gain further insight into the mechanism of IPoC, the latter was effected with 6 cycles of 10-s reperfusion/10-s reocclusion. Its protective effect was abrogated by either making the oxygenated perfusate alkaline during the reperfusion phases or making the reperfusion buffer hypoxic. Presumably the repeated coronary occlusions during IPoC keep myocardial pH low while the resupply of oxygen during the intermittent reperfusion provides fuel for the redox signaling that acts to prevent MPTP formation even after restoration of normal myocardial pH. Hearts treated simultaneously with IPoC and alkaline perfusate could not be rescued by addition to the perfusate of either PMA or SB216763 which inhibits GSK-3beta, the putative last cytoplasmic signaling step in the signal transduction cascade leading to MPTP inhibition. Yet cyclosporin A which also inhibits MPTP formation does rescue hearts made alkaline during IPoC. In view of prior studies in which the ROS scavenger N-2-mercaptopropionyl glycine aborts IPoC's protection, our data reveal that IPoC's reperfusion periods are needed to support redox signaling rather than improve metabolism. The low pH, on the other hand, is equally necessary and seems to suppress MPTP directly rather than through upstream signaling.
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PMID:Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning's success. 1862 79

The purpose of this study was to determine whether exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase-3beta (GSK-3beta). The treatment of cardiac H9c2 cells with ZnCl2 (10 microM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3beta phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3beta in H9c2 cells. The effect of zinc on GSK-3beta activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 but not by the mammalian target of rapamycin (mTOR) inhibitor rapamycin or the PKC inhibitor chelerythrine, implying that PI3K but not mTOR or PKC accounts for the action of zinc. In support of this interpretation, zinc induced a significant increase in Akt but not mTOR phosphorylation. Further experiments found that zinc also increased mitochondrial GSK-3beta phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3beta phosphorylation was not altered by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. Zinc applied at reperfusion reduced cell death in cells subjected to simulated ischemia/reperfusion, indicating that zinc can prevent reperfusion injury. However, zinc was not able to exert protection in cells transfected with the constitutively active GSK-3beta (GSK-3beta-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3beta. Cells transfected with the catalytically inactive GSK-3beta (GSK-3beta-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3beta inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3beta. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3beta. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3beta by zinc.
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PMID:Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3beta. 1911 35

Loss of retinal ganglion cells occurs in a variety of pathological conditions, including central retinal artery occlusion, diabetes and glaucoma. Using an experimental model of retinal ischemia induced by transiently raise the intraocular pressure (IOP), In this study, we report the original observation that ischemic retinal ganglion cells death is associated with the transient deactivation of the pro-survival kinase Akt and activation of GSK-3beta followed, during reperfusion, by a longer lasting, PI3K-dependent, activation of Akt and phosphorylation of GSK-3beta. Under these experimental conditions, retinal ischemia induced the expression of Bad, a pro-apoptotic protein, member of the Bcl-2 family. The detrimental effects yielded by the ischemic stimulus were minimized by intravitreal administration of the NMDA receptor antagonist, MK801, that reduced the expression of Bad and significantly increased Akt phosphorylation. In conclusion, our present results contribute to unravel the mechanisms underlying retinal damage by high IOP-induced transient ischemia in rat. In addition, these data implicate the pro-survival PI3K/Akt pathway and the observed reduced expression of Bad in the neuroprotection afforded by MK801.
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PMID:Modulation of pro-survival and death-associated pathways under retinal ischemia/reperfusion: effects of NMDA receptor blockade. 1880 92

Resveratrol pretreatment can protect the heart by inducing pharmacological preconditioning. Whether resveratrol protects the heart when applied at reperfusion remains unknown. We examined the effect of resveratrol on myocardial infarct size when given at reperfusion and investigated the mechanism underlying the effect. Isolated rat hearts were subjected to 30 min ischemia followed by 2 h of reperfusion, and myocardial samples were collected from the risk zone for Western blot analysis. Mitochondrial swelling was spectrophotometrically measured as a decrease in absorbance at 520 nm (A(520)). Resveratrol reduced infarct size and prevented cardiac mitochondrial swelling. Resveratrol enhanced GSK-3beta phosphorylation upon reperfusion, an effect that was mediated by the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway. Resveratrol translocated GSK-3beta from cytosol to mitochondria via the cGMP/PKG pathway. Further studies showed that mitochondrial GSK-3beta was co-immunoprecipitated with cyclophilin D but not with VDAC (voltage dependent anion channel) or ANT (adenine nucleotide translocator). These data suggest that resveratrol prevents myocardial reperfusion injury presumably by targeting the mPTP through translocation of GSK-3beta from cytosol to mitochondria. Translocated GSK-3beta may ultimately interact with cyclophilin D to modulate the mPTP opening.
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PMID:Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore. 1913 50

It is becoming increasingly clear that mitochondrial dysfunction is critically important in myocardial ischemic injury, and that cardioprotective mechanisms must ultimately prevent or attenuate mitochondrial damage. Mitochondria are also essential for energy production, and therefore prevention of mitochondrial injury must not compromise oxidative phosphorylation during reperfusion. This review will focus on one mitochondrial mechanism of cardioprotection involving inhibition of adenine nucleotide transport across the outer mitochondria membrane under de-energized conditions. This slows ATP hydrolysis by the mitochondria, and would be expected to lower mitochondrial membrane potential during ischemia, to inhibit calcium uptake during ischemia, and potentially to reduce free radical generation during early reperfusion. Two interventions that similarly inhibit mitochondrial adenine nucleotide transport are Bcl-2 overexpression and GSK inhibition. A possible final common mechanism shared by both of these interventions is discussed.
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PMID:Cardioprotection and altered mitochondrial adenine nucleotide transport. 1924 42

GSK-3 is constitutively active in nonstimulated cells; multiple signalings negatively regulate GSK-3 via GSK-3 phosphorylation, subcellular (i.e. cytoplasmic; nuclear; mitochondrial) localization, and interaction with other proteins. GSK-3 alpha (51 kDa)/-3 beta (47 kDa) are encoded by different genes. Dysregulated hyperactivity of GSK-3 is associated with various diseases; in vivo and in vitro studies have increasingly implicated that GSK-3 inhibitors are promising therapeutics in diabetes mellitus, inflammation, tumorigenesis, psychiatric/neurodegenerative diseases, ischemia, and stem cell regeneration. Importantly, GSK-3 is the common target for various classical therapeutic drugs. In adrenal chromaffin cells, GSK-3 inhibition caused up-regulation of voltage-dependent Nav1.7 sodium channel, enhancing voltage-dependent calcium channel gating and catecholamine exocytosis; conversely, chronic treatment with GSK-3 inhibitors caused down-regulation of insulin receptor, IRS-1, IRS-2, and Akt1 levels. In this review, I will focus on these recent topics. Comprehensive review articles about lithium (1), GSK-3 and GSK-3 inhibitors (2-4), and the inhibition of Wnt/GSK-3beta>/beta-catenin signaling pathway by therapeutic drugs (5) are useful. Chemical structures of GSK-3 inhibitors are listed in the review articles (2, 4).
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PMID:GSK-3 inhibitors and insulin receptor signaling in health, disease, and therapeutics. 1927 46

Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). Cotreatment with ERK inhibitor PD98059 abrogated sildenafil-induced protection (31.8 +/- 4.4%). To further evaluate the role of ERK in delayed cardioprotection, mice were treated with sildenafil (ip) 24 h before global ischemia-reperfusion. PD98059 was administered (ip) 30 min before sildenafil treatment. Infarct size was reduced from 27.6 +/- 3.3% in controls to 7.1 +/- 1.5% in sildenafil-treated mice (P < 0.05). The delayed protective effect of sildenafil was also abolished by PD98059 (22.5 +/- 2.3%). Western blots revealed that sildenafil significantly increased phosphorylation of ERK1/2 and GSK-3beta and induced iNOS, eNOS, Bcl-2, and PKG activity in the heart 24 h after treatment. PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.
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PMID:ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice. 1934 60

Postconditioning (PostC) may limit mitochondrial damage and apoptotic signaling. We studied markers of apoptosis and mitochondrial protection in isolated rat hearts, which underwent a) perfusion without ischemia (Sham), b) 30-min ischemia (I) plus 2-hour reperfusion (R), or c) PostC protocol (5 intermittent cycles of 10-s reperfusion and 10-s ischemia immediately after the 30-min ischemia). Markers were studied in cytosolic (CF) and/or mitochondrial (MF) fractions. In CF, while pro-apoptotic factors (cytochrome c and caspase-3) were reduced, the anti-apoptotic markers (Bcl-2 and Pim-1) were increased by PostC, compared to the I/R group. Accordingly, phospho-GSK-3beta and Bcl-2 levels increased in mitochondria of PostC group. Moreover, I/R reduced the level of mitochondrial structural protein (HSP-60) in MF and increased in CF, thus suggesting mitochondrial damage and HSP-60 release in cytosol, which were prevented by PostC. Electron microscopy confirmed that I/R markedly damaged cristae and mitochondrial membranes; damage was markedly reduced by PostC. Finally, total connexin-43 (Cx43) levels were reduced in the CF of the I/R group, whereas phospho-Cx43 level resulted in higher levels in the MF of the I/R group than the Sham group. PostC limited the I/R-induced increase of mitochondrial phospho-Cx43. Data suggest that PostC i) increases the levels of anti-apoptotic markers, including the cardioprotective kinase Pim-1, ii) decreases the pro-apoptotic markers, e.g. cytochrome c, iii) preserves the mitochondrial structure, and iv) limits the migration of phospho-Cx43 to mitochondria.
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PMID:Postconditioning induces an anti-apoptotic effect and preserves mitochondrial integrity in isolated rat hearts. 2970 30

Dysregulation of Akt signaling is important in a broad range of diseases that includes cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. We found that global ischemia in intact rats triggered expression and activation of the Akt inhibitor CTMP (carboxyl-terminal modulator protein) in vulnerable hippocampal neurons and that CTMP bound and extinguished Akt activity and was essential to ischemia-induced neuronal death. Although ischemia induced a marked phosphorylation and nuclear translocation of Akt, phosphorylated Akt was not active in post-ischemic neurons, as assessed by kinase assays and phosphorylation of the downstream targets GSK-3beta and FOXO3A. RNA interference-mediated depletion of CTMP in a clinically relevant model of stroke restored Akt activity and rescued hippocampal neurons. Our results indicate that CTMP is important in the neurodegeneration that is associated with stroke and identify CTMP as a therapeutic target for the amelioration of hippocampal injury and cognitive deficits.
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PMID:The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. 1934 76


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