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 authors tested the hypothesis that ischemia stimulates glucose uptake in rat heart independent of the insulin signaling pathway and independent of endogenous catecholamines. Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing [2-3H]glucose (5 mmol/l, 0.05 muCi/ml) and Na-oleate (0.4 mmol/l) with or without the phosphatidylinositol 3-kinase inhibitor wortmannin (3 mumol/l). Insulin (1 mU/ml) was added to the perfusate in the middle of the experiments or the hearts were subjected to 30 min of low-flow ischemia (75% reduction in coronary flow) followed by 15 min of reperfusion. In a separate group, hearts were subjected to ischemia and reperfusion in the presence of propranolol (10 mumol/l) plus phentolamine (10 mumol/l). Cardiac power was stable but decreased (-75%) during ischemia. Both insulin and ischemia increased glucose uptake (P < 0.01). Glucose uptake returned to pre-ischemic values during reperfusion. Wortmannin completely inhibited insulin-stimulated glucose uptake and glycogen synthesis, but did not affect the ischemia-stimulated glucose uptake or glycogen resynthesis during reperfusion. Full adrenergic blockade did not abolish the ischemia-stimulated glucose uptake. The authors conclude that: (1) insulin and ischemia increase glucose uptake through different mechanisms; (2) ischemia-stimulated glucose uptake is not catecholamine mediated: and (3) glycogen resynthesis during reperfusion is independent of PI3-K.
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PMID:Ischemia-stimulated glucose uptake does not require catecholamines in rat heart. 1009 55

Myocardial glucose transport is not only facilitated by the insulin sensitive glucose transporter (GLUT) 4 but also by GLUT1. It was recently demonstrated that ischemia induces GLUT4 translocation by a mechanism distinct from the insulin-induced signaling pathway. However, the role of ischemia-mediated GLUT1 translocation and the signaling pathway involved is not yet defined. This study investigated the effects of wortmannin, a phosphatidylinositol-3 kinase (PI3kinase) inhibitor, on basal, ischemia- and insulin-stimulated GLUT1 redistribution. PI3kinase is known to participate in insulin-mediated GLUT4 translocation. Rat hearts were perfused with Krebs-Henseleit buffer containing 10 mmol/l glucose according to Langendorff and treated with/without 1 micromol/l wortmannin, 100 nmol/l insulin and 15 min no-flow ischemia. Relative subcellular distribution of GLUT1 protein was analysed using membrane fractionation and subsequent Western blotting. Both ischemia and insulin significantly increased the relative amount of GLUT1 in the plasma membrane (PM) compared to controls (41.6+/-2.8% in controls v 46.0+/-2.3% in ischemic and 51.4+/-3.9% in insulin hearts, both P<0.05) with a concomitant decrease of GLUT1 in intracellular membranes. However, the increases were moderate in view of the more than 2-fold stimulated GLUT4 translocation shown for ischemia and insulin. Although wortmannin completely inhibited insulin-induced GLUT1 translocation (42.0+/-2.0% GLUT1 on PM), it had no effect on the ischemia-induced translocation of GLUT1 (45. 4+/-1% GLUT1 on PM). Treatment with the inhibitor alone did not influence basal GLUT1 distribution. Results show that in the perfused rat heart, PI3 kinase is involved in the insulin-induced signaling leading to GLUT1 translocation but not in the ischemia-mediated signaling and basal GLUT1 trafficking. This suggests two different pathways for ischemia- and insulin-induced GLUT1 translocation as recently shown for GLUT4.
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PMID:Myocardial glucose transporter GLUT1: translocation induced by insulin and ischemia. 1040 51

In order to clarify the role of protein kinases in ischemic brain injury, the spatiotemporal expression of immunoreactive serine-threonine kinase Akt, phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK) were examined at 3, 8, or 24 h after permanent middle cerebral artery occlusion (MCAO) in rats. Weak staining for these protein kinases was found in both cortical and caudate neurons in sham controls. The staining for Akt-1 and PI3-K was increased at 3-8 h in the ischemic penumbral region and declined at 24 h. A slight induction of these kinases was observed in the ischemic core region. Robust expression of ERK was noted at 3-8 h in most neurons in the area of ischemia. At 24 h, ERK continued to be expressed in the ischemic penumbra, but decreased in the ischemic core. These findings suggest that the signaling for Akt and PI3-K are different from the ERK dependent signal transduction during ischemic brain injury.
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PMID:Immunoreactive Akt, PI3-K and ERK protein kinase expression in ischemic rat brain. 1053 May 16

In the present study we have investigated whether Akt was activated during simulated ischemia (SI) and simulated ischemia/reperfusion (SI/R) in neonatal rat cardiomyocytes. Akt was phosphorylated on both S473 and T308 residues after 10 min of simulated SI/R and remained elevated for 60 min before returning to basal levels after 2 h. No phosphorylation was observed during SI alone. SI/R-stimulated Akt activation was inhibited by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, the tyrosine kinase inhibitor genistein and the Src tyrosine kinase inhibitor PP2, indicating a requirement for tyrosine kinase activity in Akt activation. Furthermore, SB203580, a p38 MAPK inhibitor, partially inhibited Akt activation. SI/R also induced the phosphorylation of PHAS-I, a downstream Akt target, in a wortmannin-dependent manner. These results demonstrate for the first time that SI/R stimulates Akt activation via PI3-K-and Src tyrosine kinase-dependent pathways, whereas p38 MAPK appears to be involved in maintaining Akt activation.
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PMID:Activation of Akt during simulated ischemia/reperfusion in cardiac myocytes. 1077 31

The mechanism of spinal cord injury has been thought to be related with tissue ischemia, and spinal motor neuron cells are suggested to be vulnerable to ischemia. To evaluate the mechanism of such vulnerability of motor neurons, we attempted to make a reproducible model of rabbit spinal cord ischemia. Using this model, the inductions of phosphatidylinositol 3-kinase (PI3-k) and serine-threonine kinase (Akt) were investigated with immunohistochemical analyses for up to 7 days of the reperfusion following 15 min of ischemia in rabbit spinal cord. It has been demonstrated that both PI3-k and its downstream effector, Akt mediate growth factor-induced neuronal survival. Spinal cord sections from animals sacrificed at 8 h, 1, 2, and 7 days following the 15 min of ischemia were immunohistochemically evaluated using monoclonal antibodies for PI3-k and Akt. Following the 15 min of ischemia, the majority of the motor neurons showed selective cell death at 7 days of reperfusion. Immunoreactivity of PI3-k and Akt were induced at 8 h of reperfusion selectively in motor neuron cells. No glial cells and inter neurons were stained in the spinal cord sections. The activation of PI3-k and Akt protein at the early stage of reperfusion may be one of the factors responsible for the delay in neuronal death after spinal cord ischemia.
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PMID:Induction of phosphatidylinositol 3-kinase and serine-threonine kinase-like immunoreactivity in rabbit spinal cord after transient ischemia. 1127 1

We investigated the role of protein kinase C (PKC) and phosphatidylinositol 3;-kinase (PI3-K) in the signaling mechanism of cardioprotection afforded by bradykinin (BK). Coronary-perfused guinea pig ventricular muscles were subjected to 20-min no-flow ischemia and 60-min reperfusion. Pretreatment for 5 min with BK (1 microm) significantly improved the recovery of developed tension measured after 60 min of reperfusion (86.8+/-2.6%v 34.8+/-4.1% in control). Prior treatment with B2 receptor antagonist HOE 140 completely abolished the protective effect of BK (37.0+/-7.6%). The protection was reduced by either PKC inhibitor chelerythrine (CH, 58.9+/-2.2%) or PI3-K inhibitor wortmannin (WM, 59.4+/-2.5%); however, the recovery of contractility was intermediate between the BK and control groups. Nevertheless, pretreatment with CH and WM together completely eliminated the protective effect of BK (38.9+/-4.2%). The mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel blocker 5-hydroxydecanoate (5HD) significantly but partially inhibited the effect of BK (59.0+/-2.2%). Pretreatment with 5HD and CH together could not generate further inhibition (61.1+/-3.3%), while pretreatment with 5HD and WM together totally eliminated the protection (34.9+/-2.9%). We conclude that BK B2 receptors can precondition guinea pig hearts via the dual activation of PKC and PI3-K. The mitoK(ATP) channels act as downstream targets of PKC, whereas PI3-K is not associated with mitoK(ATP) channels.
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PMID:Dual signaling via protein kinase C and phosphatidylinositol 3'-kinase/Akt contributes to bradykinin B2 receptor-induced cardioprotection in guinea pig hearts. 1170 48

Ischemic preconditioning results in an immediate phase of protection against lethal ischemia/reperfusion injury that is comprised of both irreversible necrosis and programmed cell death, apoptosis. We hypothesized that preconditioning may activate putative anti-apoptotic pathways, through the induction of either phosphatidyl inositol 3-OH kinase (PI3 kinase) or p42/p44 extracellular receptor kinase, attenuating total cell death. Isolated perfused rat hearts were preconditioned with two cycles of 5 min ischemia and 10 min reperfusion. Then they were frozen for Western blot analysis or subjected to 35 min regional ischemia and 120 min reperfusion prior to infarct size assessment. Selective PI3 kinase inhibitors, wortmannin (W, 100 n M) and LY294002 (LY, 15 microM) and the p42/p44 inhibitor, PD 98059 (PD, 10 and 50 microM), were individually infused during the preconditioning protocol. One further group of hearts received both inhibitors (W and PD). The results were expressed as percentage of infarction within the risk zone. Inhibition of PI3 kinase by either W or LY partially abrogated the infarct sparing effect of ischemic preconditioning (I/R%: 44.6+/-2.7 in C, 17.6+/-2.0 in IP, vs 32.2+/-4.2 in W, and 30.9+/-2.6 in LY, P<0.05). Inhibition of ERK phosphorylation however, had no significant effect upon infarct size reduction (17.6+/-2.0 in ischemic preconditioning vs 21.4+/-3.0 in IP+10 microM PD and 15.2+/-1.4 in IP+50 microM PD, P>0.05). Western blot analysis confirmed that PD abrogated the phosphorylation of p42/p44 and LY the phosphorylation of AKT. Combined inhibition with PD+W failed to further attenuate protection (27.6+/-1.3%, P>0.1). These data appear to demonstrate that the PI3 kinase, but not the p42/p44 cascade, is implicated in early ischemic preconditioning.
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PMID:PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning. 1205 53

Substantial evidence has shown that extracellular signal-regulated kinases 1 and 2 (Erk1/2) and serine/threonine kinase (Akt) play important roles in regulating cell survival. We examined the activities of these kinases in astrocytes under ischemia in an anaerobic chamber. The level of phosphorylated Erk1/2 in astrocytes began to increase after 1 h ischemia, reached a maximum after 4 h ischemia, before decreasing from 5 to 6 h. Akt was activated later than Erk1/2. It was significantly increased after 4 h ischemia before declining steadily afterwards. Lactate dehydrogenase (LDH) assay and Hoechst nucleic staining indicated that U0126, which inhibits Erk1/2 phosphorylation, enhanced ischemia-induced cell death, whereas LY294002, which inhibits Akt phosphorylation, delayed cell death. These effects were dose-dependent. At 4 and 6 h ischemia, U0126-treated astrocytes expressed a lower level of Bcl-2 than controls. In contrast, LY294002-treated astrocytes expressed a higher level of Bcl-2 than controls as shown by Western blots. Bcl-x(L) expression level was not affected by either treatment. These data suggest that activation of the MAPK/Erk1/2 pathway might protect astrocytes from ischemic injury, but activation of the PI3-K/Akt pathway does not. The effect may involve Bcl-2 but not Bcl-x(L) expression.
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PMID:Activation of Erk1/2 and Akt in astrocytes under ischemia. 1205 31

Midkine (MK) and pleiotrophin (PTN) are low molecular weight proteins with closely related structures. They are mainly composed of two domains held by disulfide bridges, and there are three antiparallel beta-sheets in each domain. MK and PTN promote the growth, survival, and migration of various cells, and play roles in neurogenesis and epithelial mesenchymal interactions during organogenesis. A chondroitin sulfate proteoglycan, protein-tyrosine phosphatase zeta (PTPzeta), is a receptor for MK and PTN. The downstream signaling system includes ERK and PI3 kinase. MK binds to the chondroitin sulfate portion of PTPzeta with high affinity. Among the various chondroitin sulfate structures, the E unit, which has 4,6-disulfated N-acetylgalactosamine, provides the strongest binding site. The expression of MK and PTN is increased in various human tumors, making them promising as tumor markers and as targets for tumor therapy. MK and PTN expression also increases upon ischemic injury. MK enhances the migration of inflammatory cells, and is involved in neointima formation and renal injury following ischemia. MK is also interesting from the viewpoints of the treatment of neurodegenerative diseases, increasing the efficiency of in vitro development, and the prevention of HIV infection.
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PMID:Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. 1220 4

To test the hypothesis that the phosphatidylinositol 3-kinase (PI3 kinase)/protein kinase Akt signaling pathway is involved in nitric oxide (NO)-induced endothelial cell migration and angiogenesis, we treated human and bovine endothelial cells with NO donors, S-nitroso-L-glutathione (GSNO) and S-nitroso-N-penicillamine (SNAP). Both GSNO and SNAP increased Akt phosphorylation and activity, which were blocked by cotreatment with the PI3 kinase inhibitor wortmannin. The mechanism was due to the activation of soluble guanylyl cyclase because 8-bromo-cyclic GMP activated PI3 kinase and the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ) blocked NO-induced PI3 kinase activity. Indeed, transfection with adenovirus containing endothelial cell NO synthase (eNOS) or protein kinase G (PKG) increased endothelial cell migration, which was inhibited by cotransfection with a dominant-negative mutant of PI3 kinase (dnPI3 kinase). In a rat model of hind limb ischemia, adenovirus-mediated delivery of human eNOS cDNA in adductor muscles resulted in time-dependent expression of recombinant eNOS, which was accompanied by significant increases in regional blood perfusion and capillary density. Coinjection of adenovirus carrying dnPI3 kinase abolished neovascularization in ischemic hind limb induced by eNOS gene transfer. These findings indicate that NO promotes endothelial cell migration and neovascularization via cGMP-dependent activation of PI3 kinase and suggest that this pathway is important in mediating NO-induced angiogenesis.
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PMID:Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis. 1289 44


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