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)

Ischemic stress is associated with marked changes in gene expression in the hippocampus--albeit little information exists on the activation of nonabundant genes. We have examined the expression of several known genes and identified novel ones in the adult rat hippocampus after a mild, transient, hypovolemic and hypotensive, global ischemic stress. An initial differential screening using a prototype array to assess gene expression after stress followed by a suppression subtractive hybridization protocol and cDNA microarray revealed 124 nonoverlapped transcripts predominantly expressed in the CA1 rat hippocampus region in response to ischemic stress. About 78% of these genes were not detected with nonsubtracted probes. Reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization on these 124 transcripts confirmed the differential expression of at least 83. Most robustly expressed were gene sequences NFI-B, ATP1B1, RHOGAP, PLA2G4A, BAX, CASP3, P53, MAO-A, FRA1, HSP70.2, and NR4A1 (NUR77), as well as sequence tags of unknown function. New stress-related genes of similar functional motifs were identified, reemphasizing the importance of functional grouping in the analysis of multiple gene expression profiles. These data indicate that ischemia elicits expression of an array of functional gene clusters that may be used as an index for stress severity and a template for target therapy design.
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PMID:Overexpression of genes in the CA1 hippocampus region of adult rat following episodes of global ischemia. 1530 17

Genomic instability is a hallmark of cancer development and progression, and characterizing the stresses that create and the mechanisms by which cells respond to genomic perturbations is essential. Here we demonstrate that antiapoptotic BCL-2 family proteins promoted tumor formation of transformed baby mouse kidney (BMK) epithelial cells by antagonizing BAX- and BAK-dependent apoptosis. Cell death in vivo correlated with hypoxia and induction of PUMA (p53 up-regulated modulator of apoptosis). Strikingly, carcinomas formed by transformed BMK cells in which apoptosis was blocked by aberrant BCL-2 family protein function displayed prevalent, highly polyploid, tumor giant cells. Examination of the transformed BMK cells in vivo revealed aberrant metaphases and ploidy changes in tumors as early as 9 d after implantation, which progressed in magnitude during the tumorigenic process. An in vitro ischemia system mimicked the tumor microenvironment, and gain of BCL-2 or loss of BAX and BAK was sufficient to confer resistance to apoptosis and to allow for accumulation of polyploid cells in vitro. These data suggest that in vivo, even in cells in which p53 function is compromised, apoptosis is an essential response to hypoxia and ischemia in the tumor microenvironment and that abrogation of this response allows the survival of cells with abnormal genomes and promotes tumorigenesis.
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PMID:Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. 1531 31

Acute coronary occlusion results in ischemia-mediated death of cardiomyocytes. In the days and weeks following myocardial infarction (MI), left ventricular remodeling occurs that is characterized by persistent cardiomyocyte apoptosis, thinning and fibrosis at the site of infarction, ventricular chamber dilatation, and growth of remaining viable cardiomyocytes. The p38 mitogen-activated protein kinase (MAPK) signaling cascade has been implicated in the remodeling process. In this work, mice with cardiac-specific expression of a dominant negative mutant form of p38 MAPK (DN-p38alpha) were subjected to MI by occlusion of the left coronary artery. Acute ischemia area was determined by transthoracic echocardiography 2 h after MI surgery, and was found to be nearly identical in DN-p38 mice and their wild-type littermates. Seven days after MI, mice were subjected to repeat echocardiography and histological examination of infarct size. DN-p38 mice had markedly reduced infarct size and increased ventricular systolic function 7 days after MI when compared to wild-type littermates. In addition, DN-p38 mice had less cardiomyocyte apoptosis than wild-type mice in the infarct border zone. Recently, it was discovered that Bcl-X(L) deamidation occurs in vivo, and this results in Bcl-X(L) degradation that sensitizes cells to apoptosis by enhancing BAX activity. Bcl-X(L) deamidation was found to occur in the cardiac tissue of wild-type mice after MI, but was reduced in DN-p38 mice. These results establish that p38 MAPK activity is required for pathological remodeling after MI and suggest that p38 MAPK may promote cardiomyocyte apoptosis through Bcl-X(L) deamidation.
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PMID:Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. 1580 38

Apoptosis is critical for normal development and tissue homeostasis. However, its abnormal occurrence has been implicated in a number of disorders, including neurodegenerative diseases and stroke. Translocation of cytochrome c (Cyt c) from mitochondria to the cytoplasm is a key step in the initiation and/or amplification of apoptosis. Here we discuss Cyt c release in apoptosis with its impact on the CNS and review our studies of Cyt c release from isolated rat brain mitochondria in response to several insults. Calcium-induced Cyt c release, as occurs in neurons during stroke and ischemia, involves rupture of the mitochondrial outer membrane (MOM) and can be blocked by inhibitors of the mitochondrial permeability transition (mPT). Thus, inhibitors of the mPT have shown efficacy in animal models of ischemia. In contrast, proapoptotic proteins, such as BID, BAX, and BAK, induce Cyt c release independently of the mPT without lysing the MOM. Several inhibitors of BAX-induced Cyt c release have shown promise in models of CNS apoptosis. Because of their distinct mechanisms for Cyt c release, both the mPT and proapoptotic proteins should be targeted for effective clinical intervention in CNS disorders involving apoptosis.
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PMID:Cytochrome C release from CNS mitochondria and potential for clinical intervention in apoptosis-mediated CNS diseases. 1611 19

Expression of the Wnt antagonist Dickkopf-1 (DKK1) is induced during neurodegenerative processes associated with Alzheimer's Disease and brain ischemia. However, little is known about DKK1-mediated effects on neurons. We now describe that, in cultured neurons, DKK1 is able to inhibit canonical Wnt signaling, as assessed by TCF reporter assay and analysis of beta-catenin levels, and to elicit cell death associated with loss of BCL-2 expression, induction of BAX, and TAU hyperphosphorylation. Local infusion of DKK1 in rats caused neuronal cell death and astrocytosis in the CA1 region of the hippocampus and death of cholinergic neurons in the nucleus basalis magnocellularis. Both effects were reversed by systemic administration of lithium ions, which rescue the Wnt pathway by inhibiting glycogen synthase kinase-3beta. The demonstration that DKK1 inhibits Wnt signaling in neurons and causes neuronal death supports the hypothesis that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neurodegenerative disorders.
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PMID:Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1. 1691 65

Ischemia-reperfusion (IR) of the testis results in germ-cell-specific apoptosis (GCA) and a reduction in daily sperm production. This has been correlated with and is dependent upon neutrophil recruitment to the testis. In a rat model of testicular IR, this has also been correlated with an increase in reactive oxygen species (ROS). We have investigated ROS in the mouse testis after IR and determined whether the observed GCA is mediated via a mitochondrial caspase-9-dependent pathway involving the upstream mediators caspase 2 and BAX. Mice were subjected to a 2-h period of testicular ischemia followed by reperfusion. An accumulation of 8-isoprostane, a marker of oxidative stress, occurred 4 h after reperfusion. Activation of a mitochondrial dependent pathway to GCA after testicular IR was determined based on the observations that both BAX and caspase 2 translocated to the mitochondria, and that an increase occurred in cytoplasmic cytochrome c. Moreover, microinfusion of a specific caspase 9 inhibitor significantly reduced active caspase 3 after testicular IR and the number of apoptotic germ cells. These results suggest that oxidative stress products accumulate in the testis following IR and demonstrate that the observed GCA is stimulated through a mitochondrial caspase-9-dependent pathway. The identification of the germ-cell apoptotic pathway induced after testicular IR, including the key players in the pathway subsequent to ROS (BAX, caspase 9, and caspase 2), aids our understanding of IR injury in the testis and provides a wider background for the development of therapeutic interventions to rescue testis function.
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PMID:Caspase-9-dependent pathway to murine germ cell apoptosis: mediation by oxidative stress, BAX, and caspase 2. 1726 69

Lipid rafts represent a subcompartment of the plasma membrane that coordinate and regulate varieties of signaling processes while caveolins are the integral membrane protein of the lipid raft. To study the role of lipid raft in ischemic preconditioning (PC) of the heart, rat hearts were perfused by working mode and then preconditioned in absence or presence of a lipid raft disintegrator, Methyl-beta-cyclodextrin. As expected, precondition made the heart resistant to ischemia reperfusion (I/R) injury as evident by improved ventricular performance, reduced myocardial infract size and cardiomyocyte apoptosis. Cyclodextrin abolished the cardioprotection. Transmission Electron Microscopy revealed severe degeneration, swelling of mitochondria, chromatin condensation and myofibril disarray in cyclodextrin treated PC heart similar to I/R heart. In the PC hearts, there was an increased association of the proapoptotic p38MAPKalpha with caveolin-1 while there was a reduced association of anti-apoptotic p38MAPKbeta with caveolin-3 indicating that reduced amount of p38MAPKalpha and increased amount of p38MAPKbeta were available to the adapted hearts thereby generating a survival signal. In contrast, there was very weak caveolin-MAP kinase interaction in cyclodextrin treated heart. Myocardial damage was further confirmed by reduced or no expression of anti-apoptotic phospho-AKT, Bcl2, Bcl-xl and increased expression of pro-apoptotic JNK, BAX, and p53 in methyl-beta-cyclodextrin (lipid raft disintegrator) treated heart. These results indicate that lipid raft play a pivotal role in the generation of survival signal in PC or adapted heart and disintegration of lipid raft completely abolish cardioprotection.
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PMID:Essential role of lipid raft in ischemic preconditioning. 1844 21

Minocycline, a broad-spectrum antimicrobial tetracycline, acts neuroprotectively in ischemia. Recently, however, minocycline has been revealed to have ambiguous effects on nerve regeneration. Thus its effects in a rat sciatic nerve transplantation model and on cultivated Schwann cells stressed by oxygen glucose deprivation (OGD) were studied. The negative effect of minocycline on Wallerian degeneration, the essential initial phase of degeneration/regeneration after nerve injury, that was recently demonstrated, was excluded by using predegenerated nerve and Schwann cell-enriched muscle grafts, both free of Wallerian degeneration. They were compared with common nerve grafts. The principle findings were that in vitro minocycline provided protective effects against OGD-induced death of Schwann cells by preventing permeability of the mitochondrial membrane. It suppressed the OGD-mediated induction of HIF-1alpha and BAX, and stabilized/induced BCL-2. Cytochrome c release and cleavage of procaspase-3 were diminished; release and translocation of AIF and cytotoxic cleavage of actin into fractin were stopped. In common nerve grafts, minocycline, besides its direct anti-ischemic effect, hampered revascularization by down-regulation of MMP9 and VEGF prolonging ischemia and impeding macrophage recruitment. In bioartificial nerve grafts that were free of Wallerian degeneration and revealed lower immunogenicity, minocycline aided the regeneration process. Here, the direct anti-ischemic effect of minocycline on Schwann cells, which are mandatory for successful peripheral nerve regeneration, dominated the systemic anti-angiogenic/pro-ischemic effects. In common nerve grafts, however, where Wallerian degeneration is a prerequisite, the anti-angiogenic and macrophage-depressing effect is an obstacle for regeneration.
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PMID:Minocycline protects Schwann cells from ischemia-like injury and promotes axonal outgrowth in bioartificial nerve grafts lacking Wallerian degeneration. 1866 90

Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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PMID:Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia-reperfusion injury in a nuclear factor-kappaB-independent manner. 1913 39

Voltage-dependent anion channel (VDAC) is the main protein in mitochondria-mediated apoptosis, and the modulation of VDAC may be induced by the excessive release of extracellular glutamate. This study examined the role of glutamate release on VDAC-mediated apoptosis in an eleven vessel occlusion model in rats. Male Sprague-Dawley rats (250-350 g) were used for the 11 vessel occlusion ischemic model, which were induced for a 10-min transient occlusion. During the ischemic and initial reperfusion episode, the real-time monitoring of the extracellular glutamate concentration was measured using an amperometric microdialysis biosensor and the cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry. To confirm neuronal apoptosis, the brains were removed 72 h after ischemia to detect the neuron-specific nuclear protein and pro-apoptotic proteins (cleaved caspase-3, VDAC, p53 and BAX). The changes in the mitochondrial morphology were measured by atomic force microscopy. A decrease in the % of CBF was observed, and an increase in glutamate release was detected after the onset of ischemia, which continued to increase during the ischemic period. A significantly higher level of glutamate release was observed in the ischemia group. The increased glutamate levels in the ischemia group resulted in the activation of VDAC and pro-apoptotic proteins in the hippocampus with morphological alterations to the mitochondria. This study suggests that an increase in glutamate release promotes VDAC-mediated apoptosis in an 11 vessel occlusion ischemic model.
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PMID:The role of glutamate release on voltage-dependent anion channels (VDAC)-mediated apoptosis in an eleven vessel occlusion model in rats. 2120 70


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