Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis contributes, with necrosis, to the cardiac cell loss after ischemia/reperfusion injury. The apoptotic cascade is initiated either by mitochondrial damage and activation of caspase-9 or by death receptor ligation and activation of caspase-8. In the present study, performed in the isolated rat heart exposed either to ischemia alone or ischemia followed by reperfusion, cleavage of caspase-9 was observed primarily in endothelial cells. Conversely, caspase-8 cleavage was only found in cardiomyocytes, where it progressively increased throughout reperfusion. Addition of a specific caspase-9 inhibitor to the perfusate before ischemia prevented endothelial apoptosis, whereas preischemic infusion of a specific caspase-8 inhibitor affected only myocyte apoptosis. Additionally, caspase-8-mediated BID processing was observed only during reperfusion. Production of tBID then sustains mitochondrial injury and perpetuates caspase-9 activation.
...
PMID:Different signaling pathways induce apoptosis in endothelial cells and cardiac myocytes during ischemia/reperfusion injury. 1193 44

Delayed hippocampal neurodegeneration after transient global ischemia is mediated, at least in part, through the activation of terminal caspases, particularly caspase-3, and the subsequent proteolytic degradation of critical cellular proteins. Caspase-3 may be activated by the membrane receptor-initiated caspase-8-dependent extrinsic pathway and the mitochondria-initiated caspase-9-dependent intrinsic pathway; however, the precise role of these deduced apoptosis-signaling pathways in activating caspase-3 in ischemic neurons remains elusive. The authors cloned the caspase-9 gene from the rat brain and investigated its potential role in mediating ischemic neuronal death in a rat model of transient global ischemia. Caspase-9 gene expression and protease activity were extremely low in the adult brain, whereas they were developmentally upregulated in newborn rats, especially at postnatal 12 weeks, a finding consistent with the theory of an essential role for caspase-9 in neuronal apoptosis during brain development. After 15-minute transient global ischemia, caspase-9 was overexpressed and proteolytically activated in the hippocampal CA1 neurons at 8 to 72 hours of reperfusion. The temporal profile of caspase-9 activation coincided with that of cytochrome c release and caspase-3 activation, but preceded CA1 neuronal death. Immunoprecipitation experiments revealed that there was enhanced formation of Apaf-1/caspase-9 complex in the hippocampus 8 and 24 hours after ischemia. Furthermore, intracerebral ventricular infusion of the relatively specific caspase-9 inhibitor N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoro-methylketone before ischemia attenuated caspase-3-like activity and significantly enhanced neuronal survival in the CA1 sector. In contrast, inhibition of caspase-8 activity had no significant effect on caspase-3 activation or neuronal survival. These results suggest that the caspase-9-dependent intrinsic pathway may be the primary mechanism responsible for the activation of caspase-3 in ischemic hippocampal neurons.
...
PMID:Cloning and characterization of rat caspase-9: implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia. 1197 26

BH3-only proteins are a subfamily of proapoptotic Bcl-2 proteins that act upstream of the mitochondrially mediated cell death pathway, and their association with the pathogenesis of brain ischemia remains largely unknown. The authors explored the temporal profiles of the expression levels and subcellular localization of BH3-only proteins in permanent middle cerebral artery occlusion (MCAO) by Western blot analysis. They observed an increased mitochondrial distribution of Bim at 3 to 6 hours of MCAO that appeared unrelated to transcriptional upregulation, as assessed by semiquantitative reverse transcription-polymerase chain reaction. At 3 to 6 hours of MCAO, Bim immunoreactivity was enhanced in neurons and oligodendrocytes in the ischemic regions. The increased mitochondrial localization of Bim coincided with a marked cytochrome c release and preceded the peak of caspase-9 activation. The authors observed an association of Bim with the dynein intermediate chain, a major component of the dynein motor complex, in the brain using a coimmunoprecipitation assay. Cerebral ischemia induced a time-dependent significant decrease in dynein expression, which started at 3 hours of MCAO. The authors deduced that the liberation of Bim from the dynein motor complex is a likely mechanism for the increased mitochondrial localization of Bim. During MCAO, Bad did not show any change in phosphorylation state or subcellular localization.
...
PMID:Temporal profiles of the subcellular localization of Bim, a BH3-only protein, during middle cerebral artery occlusion in mice. 1214 66

Transient global ischemia reportedly results in glutamate receptor stimulation and harmful Ca(2+)-overloading, then activates some proteins involved in cell apoptosis in vivo and in vitro, but underlying mechanisms remain to be elucidated. Here we evaluated the role of N-methyl-D-aspartate (NMDA) receptor antagonist and L-type voltage-gated Ca(2+) channel (L-VGCC) antagonist in mediating the release of cytochrome c and the expression of caspase-3 precursor protein (procaspase-3). Cytochrome c release from mitochondria is a critical step in the cell apoptotic process. We examined whether cytochrome c was translocated from mitochondria to the cytosol by Western blot in rat hippocampus after 15 min global ischemia. Released cytochrome c interacts with apoptotic protease activating factor-1 and caspase-9, both of which play important roles in the cytochrome c-dependent mitochondrial pathway of apoptosis by activating caspase-3. Our studies demonstrated that the inactive precursor and active cleaved subunits of caspase-3 protease increased dramatically with the extent of reperfusion time. Following pretreatment with ketamine (a non-competitive NMDA receptor antagonist) and nifedipine (L-VGCC antagonist), cytosolic cytochrome c and the expression of procaspase-3 dramatically decreased, which might result in less neuron damage after ischemia.
...
PMID:N-methyl-D-aspartate receptor and L-type voltage-gated Ca(2+) channel antagonists suppress the release of cytochrome c and the expression of procaspase-3 in rat hippocampus after global brain ischemia. 1214 22

Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK x TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 microg of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.
...
PMID:Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia. 1232 85

Platelet activating factor (PAF) is a proinflammatory lipid mediator for inflammatory response. It is unclear whether PAF is involved in the very complex process of ischemia-reperfusion (I/R) induced mucosal apoptosis in small intestine. Intestinal I/R was induced in rats intestine by 60 min occlusion of the superior mesenteric artery, followed by a 60 min reperfusion. I/R induced mucosal apoptosis and PAF activity but inhibited PAF-acetylhydrolase activity. Increases in interleukin-6 (IL-6) and decreases in IL-10 were observed. Western blot analysis showed that I/R induced expressions of platelet endothelial cell adhesion molecule-1 (PECAM-1) and Fas and Fas ligand (FasL) proteins, cleaved Bid, and enhanced the release of cytochrome c from mitochondria to activate caspase-9. Pretreatment of PAF antagonist BN-52021 attenuated these changes, except the increase in Fas. The results showed that I/R-inhibited mucosal PAF-acetylhydrolase activity resulted in an increase of activated PAF. The activated PAF increased the mucosal IL-6 and PECAM-1, enhanced the expression of FasL but not Fas, and led to the cleavage of Bid and the release of cytochrome c from mitochondria to activate caspase-9. This finding suggests that PAF promotes mucosal apoptosis after I/R in the rat small intestine partly through FasL mediating caspase-9 active pathway.
...
PMID:Platelet-activating factor promotes mucosal apoptosis via FasL-mediating caspase-9 active pathway in rat small intestine after ischemia-reperfusion. 1270 15

Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly(ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pI) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands, thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at the periphery of the infarct core.
...
PMID:Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. 1272 25

N-Tosyl-L-phenylalanyl-chloromethyl ketone (TPCK) reduces apoptosis in vitro. Pretreatment with TPCK reduces brain injury. Would treatment after injury reduce damage? Seven-day-old rats had the right carotid artery ligated and were subjected to 2.5 h of 8% oxygen and were treated intraperitoneally 3 h after hypoxia with 10 mg/kg of TPCK or vehicle. Brain damage was measured 22 days after injury. bcl-2, bax, and cytochrome c where measured by Western blot 24 h after injury. Caspase-9 and caspase-3 activity were measured enzymatically 24 h after injury. Treatment with TPCK reduced the loss of the right hemisphere caused by injury from 27.6 +/- 2.8% SEM (vehicle, n = 56) to 19.8 +/- 2.8% (TPCK, n = 61, p < 0.05). Hypoxic ischemia increased cytosolic cytochrome c from 0.25 +/- 0.04 to 0.4 +/- 0.04 optical density (OD; p < 0.05), but TPCK had no effect (0.31 +/- 0.03 OD). TPCK reduced caspase-9 activity from 72 +/- 30 to 43 +/- 5 fluorescence units/h/mg (p < 0.05 vs. vehicle), and caspase-3 activity from 66 +/- 10 to 39 +/- 3.7 fluorescence units/h/mg (p < 0.05 vs. vehicle). Treatment with TPCK 3 h after hypoxic ischemia reduced brain infarct size. TPCK may act by reducing caspase-9 activation by cytochrome c.
...
PMID:Treatment of hypoxic-ischemic brain injury in newborn rats with TPCK 3 h after hypoxia decreases caspase-9 activation and improves neuropathologic outcome. 1287 29

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of ischemic and neurodegenerative disorders. Treatment of human SH-SY5Y neuroblastoma cells with tunicamycin, an inhibitor of protein glycosylation, rapidly induced the expression of target genes of the unfolded protein response. However, prolonged treatment also triggered a delayed, caspase-dependent cell death. Microarray analysis of gene expression changes during tunicamycin-induced apoptosis revealed that the Bcl-2 homology domain 3-only family member, Bcl-2 binding component 3/p53 upregulated modulator of apoptosis (Bbc3/PUMA), was the most strongly induced pro-apoptotic gene. Expression of Bbc3/PUMA correlated with a Bcl-xL-sensitive release of cytochrome c and the activation of caspase-9 and -3. Increased expression of Bbc3/PUMA was also observed in p53-deficient human cells, in response to the ER stressor thapsigargin, and in rat hippocampal neurons after transient forebrain ischemia. Overexpression of Bbc3/PUMA was sufficient to trigger apoptosis in SH-SY5Y neuroblastoma cells, and human cells deficient in Bbc3/PUMA showed dramatically reduced apoptosis in response to ER stress. Our data suggest that the transcriptional induction of Bbc3/PUMA may be sufficient and necessary for ER stress-induced apoptosis.
...
PMID:Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway. 1291 14

Nitric oxide (NO*) at low concentrations is cytoprotective for endothelial cells; however, elevated concentrations of NO* (> or =1 micromol/liter), as may be achieved during inflammatory states, can induce apoptosis and cell death. Hypoxia is associated with tissue inflammation and ischemia and, therefore, may modulate the effects of NO* on endothelial function. To examine the influence of hypoxia on NO*-mediated apoptosis, we exposed bovine aortic endothelial cells (BAEC) to (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (diethylenetriamine NONOate, DETA-NO) (1 mmol/liter) under normoxic or hypoxic conditions (pO2 = 35 mm of Hg) and measured the indices of apoptotic cell death. BAEC treated with DETA-NO under normoxic conditions demonstrated increased levels of histone-associated DNA fragments, which was confirmed by terminal dUTP nick-end labeling assay, and hypoxic conditions augmented this response. To determine whether mitochondrial dysfunction was one mechanism by which NO* initiated apoptosis under hypoxic conditions, we evaluated mitochondrial membrane potential in (Psim). Exposure to DETA-NO resulted in a decrease in Psim and concomitant release of cytochrome c and caspase-9 activation, which were enhanced by hypoxia. By utilizing Rho0 BAEC (Rho0-EC), which lack functional mitochondria, we demonstrated that dissipation of Psim was associated with increased reactive oxygen species generation and peroxynitrite formation. Moreover, in Rho0-EC we identified activation of caspase-8 as part of the mitochondrial-independent pathway of apoptosis. To establish that peroxynitrite mediated mitochondrial damage and apoptosis, we treated BAEC and Rho0-EC with the peroxynitrite scavenger uric acid and found that the indices of apoptosis were decreased significantly. These findings confirm that high flux of NO* under hypoxic conditions promotes cell death via mitochondrial damage and mitochondrial-independent mechanisms by peroxynitrite.
...
PMID:Hypoxia potentiates nitric oxide-mediated apoptosis in endothelial cells via peroxynitrite-induced activation of mitochondria-dependent and -independent pathways. 1459 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---