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)

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%) when compared with either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.
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PMID:Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. 1077 46

Analysis of gene expression in a mouse model of unilateral ureteral obstruction (UUO) revealed significant induction of CD14 mRNA in kidneys with obstructed ureters. Immunocytochemical analysis indicated that CD14 was upregulated in tubular epithelial cells and this upregulation was not attributable to infiltration of the kidneys by mononuclear cells. This induction of CD14 mRNA was found to occur in BALB/C, C57BL/6, C3H/HeN, and C3H/HeJ mice during UUO. Ischemia/reperfusion of kidneys also induced CD14 mRNA. Mice lacking either of the tumor necrosis factor-alpha receptor (TNFR) genes were also studied; the induction of CD14 was blunted in TNFR 1-knockout mice but not in TNFR2-knockout mice. Apoptosis of tubular cells in lipopolysaccharide-resistant CH3/HeJ mice was significantly (P: < 0. 05) less than that in lipopolysaccharide-responsive CH3/HeN mice during UUO. These results suggest that CD14 is acutely induced in tubular epithelial cells in two mouse models of renal injury. This induction is regulated by tumor necrosis factor-alpha, through TNFR1. CD14 may participate in the apoptosis of tubular epithelial cells on a more chronic basis by activating a pathway that is absent or deficient in C3H/HeJ mice.
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PMID:Induction of CD14 in tubular epithelial cells during kidney disease. 1096 93

We examined the expression of tumor necrosis factor-alpha (TNF-alpha) and the Type I tumor necrosis factor receptor, (TNFR1), in relation to c-fos, a known regulator gene of immediate cellular responses, after an extended period of global ischemia. The number of TNF-alpha mRNA expressing cells peaked in most brain areas after 8 h of reperfusion. Significant increases in TNFR1 mRNA expression were evident in the cortex at 2 and 8 h of reperfusion and after 8 h of reperfusion in the CA3/CA4 region of the hippocampus. Transient neuronal c-fos mRNA expression preceded these responses. TNF-alpha immunoreactivity was seen in neurons>>>oligodendrocytes=perivascular cells=ependymal cells=vessel wall structures. After ischemia/reperfusion, increased TNF-alpha immunoreactivity was evident only in oligodendrocytes. TNFR1 immunoreactivity in sham brains manifested in bundles of cellular fibers of variable length and thickness. In post-ischemic brains, immunoreactivity in these cellular processes representing mainly astroglial extensions was suppressed at 2 h but recovered partially by 8 and 24 h of reperfusion. In contradiction, transient ischemia-induced TNFR1 immunoreactivity was observed in somas of large cortical neurons, in activated microglia/macrophages, perivascular and endothelial cells.Taken together, the increase in neuronal TNF-alpha mRNA appeared not to be followed by substantial translation to protein in the cerebral tissue after an extended period of global ischemia. However, there was increased neuronal TNFR1 immunostaining in conjunction with increased immunostaining for TNF-alpha in oligoglial elements, which suggests signaling to neurons by enhanced oligoglial TNF-alpha.
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PMID:Differential cellular expression of tumor necrosis factor-alpha and Type I tumor necrosis factor receptor after transient global forebrain ischemia. 1141 77

Tumor necrosis factor (TNF) alpha is a critical mediator of inflammation; however, TNFalpha is rarely released alone and the "cross-talk" between different classes of inflammatory mediators is largely unexplored. Thromboxane A(2) (TXA(2)) is released during I/R injury and exerts its effects via a G protein-linked receptor (TP). In this study, we found that TXA(2) mimetics stimulate leukocyte adhesion molecule (LAM) expression on endothelium via TPbeta. The potential interaction between TXA(2) and TNFalpha in altering endothelial survival and LAM expression was examined. IBOP, a TXA(2) mimetic, attenuated TNFalpha-induced LAM expression in vitro, in a concentration-dependent manner, by preventing TNFalpha-enhanced gene expression, and also reduced TNFalpha-induced leukocyte adhesion to endothelium both in vitro and in vivo. IBOP abrogated TNFalpha-induced NFkappaB activation in endothelial cells, as determined by reduced IkappaB phosphorylation and NFkappaB nuclear translocation, by inhibiting the assembly of signaling intermediates with the intracellular domain of TNF receptors 1 and 2 in response to TNFalpha. This inhibition resulted from the Galpha(q)-mediated enhancement of STAT1 activation and was reversed by anti-STAT1 antisense oligonucleotides. TNFalpha-mediated TNFR1-FADD association and caspase 8 activation were not inhibited by IBOP co-stimulation, however, resulting in a 2.6-fold increase in endothelial cell apoptosis. By stimulating the vessel wall and inducing endothelial cell apoptosis, TXA(2), in combination with TNFalpha, may hamper the angiogenic response during inflammation or ischemia, thus reducing revascularization and tissue viability.
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PMID:Inhibition of tumor necrosis factor alpha-mediated NFkappaB activation and leukocyte adhesion, with enhanced endothelial apoptosis, by G protein-linked receptor (TP) ligands. 1251 20

Intercellular adhesion molecule-1 (ICAM-1) is expressed after brain ischemia and is participated in the induction of neuronal cell death. Recently, we have reported that ICAM-1 is localized in astrocytes in the chronic phase of ischemia. However, the regulation of astroglial ICAM-1 after brain ischemia is not elucidated in detail. Therefore, we examined the gene and protein expression of TNFR1 after transient middle cerebral artery occlusion (tMCAO) by using real time-PCR and immunohistochemistry. Moreover, we determined the relationship of TNFR1 and ICAM-1 in the astrocyte in chronic phase of ischemia. Increased expression of TNFR1 mRNA in the ipsilateral cortex was noted slightly during ischemia and was significantly increased at 12 h after reperfusion. Few TNFR1-like imuunoreactivity (TNFR1-LI) was observed in the cortex of normal animals. However, TNFR1-LI was increased at 1 h during ischemia, then it was decreased at 3-6 h, and was increased again at 12-24 h after reperfusion in the core of ischemic area. TNFR1-LI was demonstrated in both neurons and astrocytes but not in oligodendrocytes and microglia/macrophages at 24 h after reperfusion. At 96 h after tMCAO, TNFR1-LI was increased in the perifocal region and it appeared to be displayed the astrocyte-like cells. By use of double immunostaining method, we found that the ICAM-1-LI was overlapped with GFAP-LI. Our data indicates that the expression of TNFR1 is up-regulated in accordance with ischemic insult and delayed expressed TNFR1-LI co-localized with ICAM-1-LI in astrocytes after tMCAO. These results suggest that astroglial ICAM-1 is regulated by TNF-alpha dependent pathway.
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PMID:Delayed expressed TNFR1 co-localize with ICAM-1 in astrocyte in mice brain after transient focal ischemia. 1548 12

To determine how cytokine transport systems at the blood-brain barrier (BBB) participate in stroke progression and recovery, we generated a mouse model of transient middle cerebral artery occlusion (tMCAO). After 1 h of occlusion followed by nearly complete reperfusion, the neurological deficits lasted more than a week as shown by several behavioral tests. Despite the prominent infarct area indicated by reduced cerebral perfusion and confirmed by vital staining, the volume of distribution of (131)I-albumin in various brain regions was not significantly altered over time (12 h to 14 days). In sharp contrast, the blood-to-brain permeation of 125I-TNFalpha was significantly increased 5 days after tMCAO. Furthermore, excess unlabeled TNFalpha abolished this enhanced 125I-TNFalpha uptake. Thus, not only did the known saturable transport system for TNFalpha persist, but it functioned at a higher capacity in tMCAO mice. Upregulation of TNFR1 and TNFR2 partially explains the increased transport, as mRNA for both receptors showed the most pronounced increase (15-fold and 30-fold, respectively) in the ischemic hemisphere 5-7 days after tMCAO. However, even in the hemisphere contralateral to the ischemia induced by stroke, there was increased TNFalpha transport. The bilateral increase in 125I-TNFalpha entry from blood to brain suggests that TNFalpha trafficking in cerebral endothelial cells is influenced by global mediators in addition to the transporting receptors. Given the known multiple modulatory effects of TNFalpha after stroke, the results indicate that the TNFalpha transport system at the BBB facilitates neuroplasticity and plays an important role in stroke recovery.
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PMID:Stroke upregulates TNFalpha transport across the blood-brain barrier. 1641 21

A short ischemic event (ischemic preconditioning) can result in subsequent resistance to severe ischemic injury (ischemic tolerance). Glutamate is released after ischemia and produces cell death. It has been described that after ischemic preconditioning, the release of glutamate is reduced. We have shown that an in vitro model of ischemic preconditioning produces upregulation of glutamate transporters which mediates brain tolerance. We have now decided to investigate whether ischemic preconditioning-induced glutamate transporter upregulation takes also place in vivo, its cellular localization and the mechanisms by which this upregulation is controlled. A period of 10 min of temporary middle cerebral artery occlusion was used as a model of ischemic preconditioning in rat. EAAT1, EAAT2 and EAAT3 glutamate transporters were found in brain from control animals. Ischemic preconditioning produced an up-regulation of EAAT2 and EAAT3 but not of EAAT1 expression. Ischemic preconditioning-induced increase in EAAT3 expression was reduced by the TNF-alpha converting enzyme inhibitor BB1101. Intracerebral administration of either anti-TNF-alpha antibody or of a TNFR1 antisense oligodeoxynucleotide also inhibited ischemic preconditioning-induced EAAT3 up-regulation. Immunohistochemical studies suggest that, whereas the expression of EAAT3 is located in both neuronal cytoplasm and plasma membrane, ischemic preconditioning-induced up-regulation of EAAT3 is mainly localized at the plasma membrane level. In summary, these results demonstrate that in vivo ischemic preconditioning increases the expression of EAAT2 and EAAT3 glutamate transporters the upregulation of the latter being at least partly mediated by TNF-alpha converting enzyme/TNF-alpha/TNFR1 pathway.
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PMID:TNFR1 mediates increased neuronal membrane EAAT3 expression after in vivo cerebral ischemic preconditioning. 1644 37

Whereas stress is known to be one of the risk factors of stroke, few experimental studies have examined the possible mechanisms by which stress may affect stroke outcome. Most of the knowledge on the effects of stress on cerebrovascular disease in humans is restricted to catecholamines and glucocorticoids effects on blood pressure and/or development of atherosclerosis. By using an experimental paradigm consisting of the exposure of Fischer rats to repeated immobilization sessions (1 h daily during seven consecutive days) prior to permanent middle cerebral artery occlusion (MCAO), we have found that stress worsens behavioral outcome and increases infarct size after MCAO. These changes occur concomitantly to an increase in inducible nitric oxide synthase (iNOS) expression and to the accumulation of lipid peroxidation markers in brain tissue. The possible regulatory role of TNFalpha was studied by looking at the mechanisms of release of this cytokine as well as to the expression of its receptors (TNFR1 and 2). The results of the present study suggest an increase in TNFalpha expression and release after stress, as well as an increase in the expression of TNFR1. Pharmacological blockade of TNFalpha with anti-TNFalpha led to a decrease in the infarct size as well as in the oxidative/nitrosative biochemical parameters seen after ischemia. In summary, our results indicate that TNFalpha accounts, at least partly, for the worsening of MCAO consequences in brain of rats exposed to stress. Furthermore, the data presented here provide evidence that stress can increase brain ischemic damage and support a possible protective effect of treatment of stressful situations before and during the development of the brain ischemia.
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PMID:The role of tumor necrosis factor-alpha in stress-induced worsening of cerebral ischemia in rats. 1684 5

We have previously shown that tumor necrosis factor (TNF) acts via its two receptors TNFR1 and TNFR2 to elicit distinct signaling pathways in vascular endothelial cells (ECs). Here we used a femoral artery ligation model to demonstrate that TNFR1-knockout (KO) mice had enhanced, whereas TNFR2-KO had reduced, capacity in clinical recovery, limb perfusion, and ischemic reserve capacity compared with the wild-type mice. Consistently, ischemia-initiated collateral growth (arteriogenesis) in the upper limb and capillary formation and vessel maturation (angiogenesis) in the lower limb were enhanced in TNFR1-KO but were reduced in TNFR2-KO mice. Furthermore, our results suggest that vascular proliferation, but not infiltration of macrophages and lymphocytes, accounted for the phenotypic differences between the TNFR1-KO and TNFR2-KO mice. In wild-type animals TNFR2 protein in vascular endothelium was highly up-regulated in response to ischemia, leading to increased TNFR2-specific signaling as determined by the formation TNFR2-TRAF2 complex and activation of TNFR2-specific kinase Bmx/Etk. In isolated murine ECs, activation of TNFR2 induced nuclear factor-kappaB-dependent reporter gene expression, EC survival, and migration. In contrast, activation of TNFR1 caused inhibition of EC migration and EC apoptosis. These data demonstrate that TNFR1 and TNFR2 play differential roles in ischemia-mediated arteriogenesis and angiogenesis, partly because of their opposite effects on EC survival and migration.
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PMID:Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis. 1707 9

TNFalpha is a cytokine wit pleiotropic functions in many organs. In the heart increased TNFalpha levels are not only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNFalpha in the heart is concentration-dependent, we studied two mouse heart models with low (two- to threefold) over-expression of endogenous TNFalpha: mice deficient in a translational repressor of TNFalpha mRNA, TIA-1(-/-), and mice over-expressing human TNFalpha. Hearts lacking TIA-1 were characterized for their endogenous TNFalpha over-expression during normal Langendorff perfusion. To define which TNFalpha receptor mediates cardiac protection, we also used mice lacking the TNFR1 receptor. Contractile function was assessed in isolated hearts perfused in the isovolumic Langendorff mode during and following global no-flow ischemic stress and in response to varying extracellular [Ca(2+)] to determine their contractile response and Ca(2+) sensitivity. All hearts with low over-expression of TNFalpha, independent of human or murine origin, have improved contractile performance and increased Ca(2+) sensitivity (by 0.2-0.26 pCa). Hearts lacking TNFR1 have contractile performance equal to wild type hearts. Recovery from ischemia was greater in TIA-1(-/-) and was diminished in TNFR1(-/-). Better contractile function in TNFalpha over-expressing hearts is not due to improved cardiac energetics assessed as [ATP] and glucose uptake or to differences in expression of SERCA2a or calmodulin. We suggest that low levels of TNFalpha increase the Ca(2+) sensitivity of the heart via a TNFR1-mediated mechanism.
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PMID:Low over-expression of TNFalpha in the mouse heart increases contractile performance via TNFR1. 1845 58


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