Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported previously that cultured vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR) show higher proliferation and cell death than normotensive controls. In addition to protecting cells against death, heat stress proteins (HSPs) appear to play a role in cell proliferation. This investigation examines the involvement of HSP72 and HSP27 in altered SHR VSMC proliferation and death. We have performed detailed discriminatory analysis to characterize which type of VSMC death is induced by heat stress (HS) and serum deprivation. Serum deprivation induced apoptosis (caspase-3 cleavage and DNA laddering) and secondary necrosis, the 2 processes being a continuum of each other. In contrast, acute HS (46 degrees C, 30 minutes), which inhibited BN. lx and SHR VSMC proliferation by 2-fold, increased necrosis (by 5-fold and 2-fold, respectively) but not apoptosis. HSP72 and HSP27 expression evoked in VSMC by mild HS (44 degrees C, 15 minutes) 6 hours before acute HS prevented the inhibition of proliferation and induction of necrosis with no effect on serum deprivation-induced or staurosporine-induced apoptosis. This induced expression of HSP72 and HSP27 did not eliminate the higher basal proliferation, apoptosis, and necrosis of SHR VSMC compared with BN.lx VSMC, suggesting that these HSPs are not involved in altered SHR VSMC proliferation and death. Also, although apoptosis and necrosis may be a continuum, in VSMC the 2 processes may be distinguished by HS, in which only necrosis is prevented by prior HSP accumulation. This observation may be of use in designing strategies for cellular protection.
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PMID:Protection against necrosis but not apoptosis by heat-stress proteins in vascular smooth muscle cells: evidence for distinct modes of cell death. 1008 7

Extracellular adenosine (Ado) accumulates during brain ischemia. To investigate the pathophysiological role of Ado on glial cells under ischemic conditions, we examined the effect of Ado on the survival of C6 glial cells exposed to chemical ischemia (CI). Treatment with Ado during exposure to CI showed a marked protective effect, that was mediated via intracellular transport and conversion of Ado to inosine (Ino). In contrast, Ado exacerbated CI-mediated cell death when it was added during the recovery time after exposure to CI. Ado cytotoxicity was largely mediated via intracellular transport, but conversion of Ado to Ino abolished its toxicity. Ado-induced cell death was characteristic of apoptosis, and Ado increased the expression of a pro-apoptotic product Bax but decreased that of an anti-apoptotic product Bcl-2. Ado also suppressed the induction of two stress proteins HSC70 and HSP27. Furthermore, Ado induced cytochrome c release and increased caspase-3-like activity. These results indicate the dual opposing effects of Ado on glial cell survival. Intracellular accumulation of Ado can be both cytoprotective and cytotoxic, depending on its metabolic pathway.
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PMID:Opposing effects of adenosine on the survival of glial cells exposed to chemical ischemia. 1107 Apr 97

Kainate-induced status epilepticus is associated with both apoptotic and necrotic cell death and induction of heat shock proteins (HSPs) in hippocampal and cortical regions of the rodent brain. In the present study we have examined the temporal, spatial and cellular expression patterns of mRNAs for the highly inducible HSPs, HSP70 and HSP27, together with the apoptotic marker, caspase 3 (CPP32) in rat brain after systemic administration of kainate. HSP70 mRNA was transiently induced in the forebrain by kainate, principally in the CA1, CA3 and hilar cells of the hippocampal formation, in piriform cortex and discrete thalamic nuclei. Maximal expression was seen at 8 h after kainate which then declined to background levels by 7 days. Labelling was predominantly neuronal. In contrast, HSP27 mRNA expression was more widespread. Intense labelling was observed in CA1, CA3 and the hilar region at 8 h after kainate but the expression profile for HSP27 mRNA expanded considerably with intense signals seen in corpus callosum, cortex and thalamus at 24 h post kainate. Emulsion autoradiographs indicated a predominantly glial localisation for HSP27 mRNA. In the hilus, a distinct subpopulation of interneurones were found to express HSP27 mRNA. CPP32 mRNA was upregulated in CA1, CA3 and hilus of the hippocampal formation and in piriform cortex. CPP32 mRNA expression was more restricted and similar in distribution to HSP70 mRNA being localised to neurones. The present study demonstrates the unique early expression of HSP27 mRNA by glial cells and distinct populations of neurones which extends beyond those in which HSP70 and CPP32 induction occurs with subsequent cell loss.
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PMID:Heat shock protein 27 shows a distinctive widespread spatial and temporal pattern of induction in CNS glial and neuronal cells compared to heat shock protein 70 and caspase 3 following kainate administration. 1158 92

The degeneration of nigral dopamine neurons in Parkinson's disease (PD) reportedly involves a defect in brain mitochondrial complex I in association with the activation of nuclear factor-kappaB (NF-kappaB) and caspase-3. To elucidate molecular mechanisms possibly linking these events, as well as to evaluate the neuroprotective potential of the cyclopentenone prostaglandin A1 (PGA1), an inducer of heat shock proteins (HSPs), we exposed human dopaminergic SH-SY5Y cells to the complex I inhibitor rotenone. Dose-dependent apoptosis was preceded by the nuclear translocation of NF-kappaB and then the activation of caspase-3 over the ensuing 24 h. PGA1 increased the expression of HSP70 and HSP27 and protected against rotenone-induced apoptosis, without increasing necrotic death. PGA1 blocked the rotenone-induced nuclear translocation of NF-kappaB and attenuated, but did not abolish, the caspase-3 elevation. Unexpectedly, the caspase-3 inhibitor, Ac-DEVD.CHO (DEVD), at a concentration that completely prevented the caspase-3 elevation produced by rotenone, failed to protect against apoptosis. These results suggest that complex I deficiency in dopamine cells can induce apoptosis by a process involving early NF-kappaB nuclear translocation and caspase-3 activation. PGA1 appears to protect against rotenone-induced cell death by inducing HSPs and blocking nuclear translocation of NF-kappaB in a process that attenuates caspase-3 activation, but is not mediated by its inhibition.
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PMID:Prostaglandin A1 inhibits rotenone-induced apoptosis in SH-SY5Y cells. 1243 80

5-Aminolaevulinic acid-based photodynamic therapy (ALA-PDT) is used to eliminate cancerous cells through photoactivation of endogenously formed protoporphyrin IX (PPIX) following the administration of PPIX precursor, 5-aminolaevulinic acid (ALA). We report on the kinetics of PPIX accumulation and the mechanism of cytotoxic effects of ALA-PDT studied in the chronic myelogenous leukaemia derived cell line K562. The PPIX distribution and, consequently, cytotoxic effects were found to be heterogenous. A subpopulation of K562 cells accumulating PPIX to a lesser extent exhibits only transient cell cycle arrest. A fraction of cells, probably those with higher PPIX accumulation, are irreversibly damaged by ALA-PDT. We detected several signs of an early apoptosis: lowering of Bcl-xL expression, decrease of the mitochondrial and plasma membrane potential, the cytochrome c release into the cytoplasm, and the unmasking of the mitochondrial antigen 7A6. However, late apoptotic events were lacking: neither caspase-3 activation nor DNA fragmentation occurred. Instead, rapidly progressing cell necrosis resulting from plasma membrane damage was observed. We suggest that the high level of the antiapoptotic heat-shock proteins HSP70 and HSP27 found by us in the K562 cells is responsible for the inhibition of the apoptotic process upstream of caspases activation.
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PMID:Early apoptotic features of K562 cell death induced by 5-aminolaevulinic acid-based photodynamic therapy. 1473 53

Newborn piglets were submitted to normobaric hypoxia (5% O2, 95% N2) for either 1 or 4 h. The effects of hypoxia on the neonatal brain were characterized through a time-course analysis of levels of various proteins such as heat shock proteins (HSP27, 70, and 90), hypoxia inducible factor-1alpha (HIF-1alpha), neuronal nitric oxide synthase (nNOS), hemeoxygenase-2 (HO-2), and caspase-3. The expression of these proteins was determined at different stages of recovery up to 72 h in cerebellum, cortex, and hippocampus by Western blot analysis in hypoxic maintained animals that were made hypoxic at either 20 or 37 degrees C. In all regions of the brain, HIF-1alpha and HSP27 expression were strongly increased until 22 h of recovery. No significant changes were observed for HSP70, HSP90, and HO-2. A small elevation of expression of nNOS was observed at early stages in the cerebellum and the cortex with no change in the hippocampus. Expression of caspase 3 was strongly increased in the cortex 24 and 48 h after hypoxia but unchanged in the hippocampus. These results are presented in terms of the porcine model of nonischemic hypoxia and its delayed neuronal effects on the cerebral outcome. Because of their recently established biochemical and functional interactions, the expression of the main HSPs, HIF-1alpha, nNOS, and caspase-3 after hypoxia are delineated.
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PMID:Effects of hypoxia on stress proteins in the piglet brain at birth. 1537 67

Treatment for 14 to 24 hours with low concentrations of arsenic trioxide (As2O3, 1-4 microM) caused apoptosis in U-937 promonocytes and other human myeloid leukemia cell lines (HL-60, NB4). This effect was potentiated by cotreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin, and the Akt inhibitor Akt(i)5. However, the inhibitors did not increase the toxicity of the mitochondria-targeting drug lonidamine, and the DNA-specific drugs camptothecin and cisplatin, when used under similar experimental conditions as As2O3. The potentiation of As2O3-provoked apoptosis involved the increased disruption of mitochondrial transmembrane potential, increased caspase-3 activation and cytochrome c release from mitochondria, increased Bax and Bid activation, and attenuation of 27-kDa heat shock protein (HSP27) expression; the potentiation was prevented by Bcl-2 overexpression. The PI3K/Akt inhibitors decreased the intracellular glutathione content, and caused intracellular oxidation, as measured by peroxide accumulation. Cotreatment with subcytotoxic concentrations of hydrogen peroxide increased apoptosis induction by As2O3. On the other hand, the treatments did not significantly affect glutathione S-transferase pi expression and activity. These results, which indicate that glutathione is a target of PI3K/Akt in myeloid leukemia cells, may partially explain the selective increase of As2O3 toxicity by PI3K/Akt inhibitors, and may provide a rationale to improve the efficacy of these inhibitors as therapeutic agents.
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PMID:Pharmacologic inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells. 1566 16

The adaptation of renal medullary cells to their hyperosmotic environment involves the accumulation of compatible organic osmolytes and the enhanced synthesis of heat shock proteins (HSP) 27 and 70. While the mechanisms leading to osmolyte accumulation are similar in papillary collecting duct (PCD) and papillary interstitial (PI) cells, the present data demonstrate that HSP27 and HSP70 are expressed differentially in these cells both in vivo and in vitro. HSP70 is abundant in PCD, but not expressed in PI cells in the papilla in situ, while HSP27 is expressed in both PCD and PI cells. These observations could be reproduced by non-permeant solutes in cultured cells. Osmotic stress strongly induced HSP70 in MDCK cells (as a model for PCD cells), but not in PI cells, while HSP27 was constitutively expressed in MDCK cells and was up-regulated in PI cells. Since prior hypertonic stress (NaCl addition) protects MDCK against subsequent exposure to high urea concentrations, this effect was also assessed in PI cells. In both cell lines, hypertonic pretreatment prior to urea exposure (400 mm) strongly attenuated caspase-3 activation. Inhibition of HSP27 expression by antisense transfection diminished the protective effect of hypertonic preconditioning in PI cells, while attenuation of HSP70 expression in MDCK cells diminished the protective effect of hypertonic preconditioning in these cells. These observations indicate that PCD and PI cells employ cell-specific mechanisms for protection against high urea concentrations as present in the renal papilla during antidiuresis.
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PMID:Differential expression of heat shock protein 27 and 70 in renal papillary collecting duct and interstitial cells - implications for urea resistance. 1571 62

Aging of skeletal muscle is often accompanied by muscle atrophy and it appears that apoptosis plays an important role in this process. The detailed mechanism(s) is not completely understood, however. In this study, we examined expression of the apoptosis regulatory proteins as well as the heat shock proteins, which have been shown to modulate the apoptotic process in certain cell types, in order to more completely elucidate apoptotic signaling in aged skeletal muscle. To more specifically identify alterations that are likely to be the result of aging, we compared 16-month-old middle-aged (MD) and 29-month-old senescent (SE) male Fischer 344 x Brown Norway rats in our study. Our results show that the degree of DNA laddering was higher in SE compared to MD rats. Using total tissue homogenates we examined the level of expression of several apoptosis-related proteins in two categories: mitochondria-associated proteins and caspases. Of the mitochondria-associated proteins, the levels of p53 showed a significant increase in SE compared to MD rats. There was also a significant increase in the expression of Bax, Bcl-2 and Apaf-1 in SE rats over that of MD rats; cytochrome c and AIF levels remained unchanged, however. Regarding the caspases, there were increases in the levels of pro-caspases-12 and -7 and cleaved caspase-9, although the levels of pro- and cleaved caspase-3 as well as cleaved caspase-12 remained unchanged. Furthermore, our results showed significant increases in HSP27, HSP60, and the inducible HSP70. These data show that in rat skeletal muscle increased apoptosis occurs between middle-age and senescence, indicating an aging-related increase in apoptosis in skeletal muscle. The involvement of different apoptotic pathways in the aging process is suggested by the selective alterations in the apoptosis regulatory proteins. The increased expression of the HSPs suggests a relationship between HSPs and the aging-related apoptotic process.
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PMID:Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle. 1613 96

Several groups have reported apoptosis of dorsal root ganglion (DRG) cells as a prominent feature of diabetic polyneuropathy (DPN), although this has been controversial. Here, we examined subacute (4-month) type 1 diabetic BB/Wor rats with respect to sensory nerve functions, DRG and sural nerve morphometry, pro- and antiapoptotic proteins, and the expression of neurotrophic factors and their receptors. Sensory nerve conduction velocity was reduced by 13% and was accompanied by significant hyperalgesia. The numbers of DRG neurons including substance P-and calcitonin gene-related peptide-positive neurons were not altered, although they showed significant atrophy. Sural nerve morphometry showed decreased numbers of myelinated and unmyelinated fibers. Active caspase-3 and Bax expressions were increased, whereas antiapoptotic Bcl-xl and heat shock protein (HSP) 27 expressions in DRGs were increased. Nerve growth factor (NGF) contents in sciatic nerves and the expression of NGF receptor TrkA in DRGs were decreased. Immunohistochemistry showed increased numbers of active caspase-3-, HSP70-, and HSP27-positive neurons. Examinations of DRGs revealed no structural evidence of apoptosis but rather progressive hydropic degenerative changes. We conclude that apoptotic stress is induced in DRGs but is counterbalanced by survival elements in subacute type 1 diabetic BB/Wor rats and that distal nerve fiber loss reflects a dying-back phenomenon caused by impaired neurotrophic support.
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PMID:Apoptotic stress is counterbalanced by survival elements preventing programmed cell death of dorsal root ganglions in subacute type 1 diabetic BB/Wor rats. 1624 57


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