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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report summarizes recent findings in the field of basic and translational apoptosis research which were presented at the 1st Conference on 'Mechanisms of Cell Death and Disease: Advances in Therapeutic Intervention' organized by the European School of Hematology and the University of Texas MD Anderson Cancer Center, 13-17 May, in Dublin, Ireland, and puts them in the context of the literature. Recent discoveries have significantly advanced the understanding of biochemical and genetic requirements of distinct apoptosis pathways (ie mitochondrial, death-receptor and endoplasmic reticulum-mediated apoptosis) and their dysregulation in disease. Progress has been made especially in the elucidation of the mechanisms of action of the Bcl-2 family members, in detail the formation of channels and their regulation in the mitochondrial membranes, conformational changes in Bax and Bak, and crosstalk of death receptor-triggered apoptosis to the mitochondria by activation of Bax via Bid. In addition, novel insights have been gained about the regulation of caspases and novel caspase signaling pathways, such as activation of caspase-12 by the endoplasmic reticulum stress response. Therapeutic applications of apoptosis manipulation include (1) the inhibition of caspases in acute and chronic neurodegenerative diseases, ie stroke, Alzheimer's or Huntington's disease by drugs and (2) sensitization of cancer cells for drug/radiation-induced apoptosis by modulation of survival signals and viral transfer of apoptosis promoting genes.
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PMID:Dissecting the pathways to death. 1118 90

Hypoxia/reoxygenation causes cellular injury and death associated with a number of pathophysiological conditions, including myocardial ischemia/reperfusion injury and stroke. The cell death pathways induced by hypoxia/reoxygenation and their underlying regulatory mechanisms remain poorly understood. Recent studies have shown that hypoxia/reoxygenation can induce Bax translocation and cytochrome c release. Using murine lung endothelial cells as a model, we found that the induction of apoptosis by hypoxia/reoxygenation involved the activation of both Bax-dependent and death receptor-mediated pathways. We demonstrated the activation of the death-inducing signal complex and Bid pathway after hypoxia/reoxygenation. Hepatocyte growth factor markedly inhibited hypoxia/reoxygenation-induced endothelial cell apoptosis. The cytoprotection afforded by hepatocyte growth factor was mediated in part by the stimulation of FLICE-like inhibiting protein expression, the attenuation of death-inducing signal complex formation, and the inhibition of Bid and Bax activation. Hepatocyte growth factor also prevented cell injury and death by increasing the expression of the antiapoptotic Bcl-XL protein. The inhibition of Bid/Bax-induced cell death by hepatocyte growth factor primarily involved p38 MAPK and in part Akt-dependent pathways but not ERK1/ERK2.
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PMID:Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells. 1462 9

Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.
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PMID:Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. 1558 Feb 49

Delayed neuronal cell death occurring hours after reperfusion is a hallmark of ischemic stroke and a primary target for neuroprotective strategies. In the present study, we investigated whether apoptosis-inducing factor (AIF), a caspase-independent proapoptotic protein, is responsible for neuronal cell death after glutamate toxicity and oxygen-glucose deprivation (OGD) in vitro and after experimental stroke in vivo. AIF translocated to the nucleus in which it colocalized with DNA fragmentation and nuclear apoptotic morphology after exposure to glutamate or OGD in cultured neurons or after transient middle cerebral artery occlusion (MCAo) in mice. Small inhibitory RNA-mediated downregulation of AIF reduced glutamate- and OGD-induced neuronal apoptosis by 37 and 60%, respectively (p < 0.01). Moreover, Harlequin mutant mice, which express AIF at low levels (approximately 20% of wild-type mice), displayed smaller infarct volumes (-43%; p < 0.03) and showed dramatically reduced cell death in the ischemic penumbra after 45 min of MCAo compared with wild-type littermates. Inhibition of poly(ADP-ribose) polymerase and Bid reduced nuclear AIF translocation. These results provide the first evidence for a causal role of AIF in ischemic neuronal cell death. Therefore, caspase-independent cell death signaling may provide a promising novel target for therapeutic interventions in cerebrovascular diseases.
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PMID:Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. 1626 34

Ischemia followed by reperfusion is the primary cause of tissue injury and infarction during heart attack and stroke. The initiating stimulus is believed to involve reactive oxygen species that are produced during reperfusion when electron transport resumes in the mitochondria after suppression by ischemia. Programmed death has been shown to be a significant component of infarction, and evidence indicates that multiple pathways are initiated during both ischemia and reperfusion phases. Major infarction is preceded by severe ischemia that includes hypoxia, intracellular acidosis, glucose depletion, loss of ATP, and elevation of cytoplasmic calcium. The superimposition of a reactive oxygen surge on the latter condition provides the impetus for maximal damage. Compelling evidence implicates mitochondria not only as the source of initiating ROS but also as the focal sensors that translate the redox stress signal into a cellular-death response. Pivotal to this response are the BH3-only proteins that are activated by death signals and regulate mitochondrial communication with executioner proteins in the cytoplasm. The BH3-only proteins do this by controlling the activity of pores and channels in the outer mitochondrial membrane. To date at least six BH3-only proteins have been shown to contribute to ischemia-reperfusion death pathways in heart and/or brain; these include Bnip3, PUMA, Bid, Bad, HGTD-P, and Noxa. Here we review the evidence for these cell-death pathways and discuss their relevance to ischemic disease and infarction.
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PMID:Redox stress and the contributions of BH3-only proteins to infarction. 1698 20

Sustained progression of neuronal cell death causes brain tissue loss and subsequent functional deficits following stroke or central nervous system trauma and in neurodegenerative diseases. Despite obvious differences in the pathology of these neurological disorders, the underlying delayed neuronal demise is carried out by a common biochemical cell death programme. Mitochondrial membrane permeabilization and subsequent release of apoptotic factors are key mechanisms during this process. Bcl-2 family proteins, e.g. the pro-apoptotic Bid, Bax or Bad and the antiapoptotic Bcl-2, Bcl-X(L), play a crucial role in the regulation of this mitochondrial checkpoint in neurons. In particular, cleavage of cytosolic Bid and subsequent mitochondrial translocation have been detected in many paradigms of neuronal cell death related to acute or chronic neurodegeneration. The current review focuses on the emerging role of Bid as an integrating key regulator of the intrinsic death pathway that amplifies caspase-dependent and caspase-independent execution of neuronal apoptosis. Therefore pharmacological inhibition of Bid provides a promising therapeutic strategy in neurological diseases where programmed cell death is prominent.
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PMID:Targeting Bid to prevent programmed cell death in neurons. 1707 14

The inappropriate survival of cells in the neointima contributes to atherosclerotic plaque progression, while apoptosis in the fibrous cap of lesions contributes to myocardial infarction and stroke. Prior genomic-scale transcript profiling of human carotid artery plaque cells with known sensitivity or resistance to fas-induced apoptosis identified candidate genes involved in lesion cell apoptosis. Retroviral overexpression indicated that several candidate factors were not causative, but that Bcl-X(L) conferred complete resistance to apoptosis induced by fas ligation. Resistant cells failed to efficiently activate caspase 8, an effect which was also observed in Bcl-X(L)-transfected cells. Small-molecule Bcl-2/X(L) inhibitors and siRNA knockdown of Bcl-X(L) markedly sensitized resistant cells to apoptosis, and partially restored caspase 8 activation. Caspase 3, 6 and 9 inhibitors reduced caspase 8 activation and blocked apoptosis. Complete knockdown of caspase 9 did not reduce apoptosis, while knockdown of Bid suppressed apoptosis, suggesting that mitochondrial pathways independent of caspase 9, such as Smac/Diablo or AIF, provide a necessary mitochondrial input to efficient caspase activation. Bcl-X(L) appears to modulate lesion cell apoptosis by suppressing mitochondrial amplification of caspase activation loops. The results may have direct implications for controlling plaque instability/progression, and identify a new class of small molecules to inhibit restenosis.
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PMID:Resistance to fas-induced apoptosis in cells from human atherosclerotic lesions: elevated Bcl-XL inhibits apoptosis and caspase activation. 1765 64

Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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PMID:Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. 1826 88

Ischemic cell death is a complex process and the initial distinction between apoptosis and necrosis appears to be an oversimplification. We previously reported that in ischemic neurons with disrupted plasmalemma, apoptotic mechanisms were also active. In the present study, we investigated cellular co-localization of another necrotic feature, lysosomal rupture, with apoptotic mechanisms in the mouse brain and assessed the potential interactions between cysteine proteases. The lysosomal enzymes were spilled into the cytoplasm 1-4h after ischemia/reperfusion, suggesting that lysosomal membrane integrity was rapidly lost, as occurs in necrosis. The same neurons also exhibited caspase-3 and Bid cleavage, and cytochrome-c release. Caspase-3 activity preceded cathepsin-B leakage in most neurons, and declined by 12h, while lysosomal leakage continued to increase. Concurrent inhibition of cathepsin-B and caspase-3 provided significantly better neuroprotection than obtained with separate use of each inhibitor. These data suggest that necrotic and apoptotic mechanisms may act both in concert as well as independently within the same cell beginning at the onset of ischemia to ensure the demise of damaged neurons. Therefore, combined inhibition of cysteine proteases may abrogate potential shifts between alternative death pathways and improve the success of stroke treatments.
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PMID:Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia. 2060 Sep 13

Infiltration of leukocytes into post-ischemic cerebrum is a well-described phenomenon in stroke injury. Because CD-8(+) T-lymphocytes secrete cytotoxic proteases, including granzyme-b (Gra-b) that exacerbates post-ischemic brain damage, we investigated roles of Gra-b in human stroke. To study the role of Gra-b in stroke, ischemic and non-ischemic tissues (from post-mortem stroke patients) were analyzed using immunoblotting, co-immunoprecipitation, terminal deoxy uridine nick end labeling (TUNEL) and Annexin-V immunostaining, and in vitro neuron survival assays. Activated CG-SH cells and supernatants were used to model leukocyte-dependent injury. Non-ischemic brain tissues were used as non-pathological controls. Non-activated CG-SH cells and supernatants were used as controls for in vitro experiments. Human stroke (ischemic) samples contained significantly higher levels of Gra-b and interferon-gamma inducible protein-10 (IP-10/CXCL10) than non-ischemic controls. In stroke, poly (ADP-ribose) polymerase-1 and heat shock protein-70 were cleaved to canonical proteolytic "signature" fragments by Gra-b. Gra-b was also found to bind to Bid and caspase-3. Gra-b also co-localized with Annexin-V(+) /TUNEL(+) in degenerating neurons. Importantly, Gra-b inhibition protected both normal and ischemia-reperfused neurons against in vitro neurotoxicity mediated by activated CG-SH cells and supernatants. These results suggest that increased leukocyte infiltration and elevated Gra-b levels in the post-stroke brain can induce contact-dependent and independent post-ischemic neuronal death to aggravate stroke injury.
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PMID:Role of cytotoxic protease granzyme-b in neuronal degeneration during human stroke. 2082 13


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