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PubMed2006

ER stress contributes to ischemia-induced cardiomyocyte apoptosis.

Myocardial ischemia is a severe stress condition that leads to loss of cardiomyocytes. The cell loss is attributed to apoptosis, although the exact mechanisms involved are only partially defined, which limits therapeutic opportunities. Here, we show caspase activation and apoptosis in neonatal rat cardiomyocyte cultures subjected to simulated ischemia by serum, glucose, and oxygen deprivation (SGO). Caspase activation was preceded by endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR), detected by the induction of Grp78, induction and splicing of XBP1, and phosphorylation of eukaryotic initiation factor 2-alpha (eIF2alpha). At a later time the ER stress response switched from UPR and cytoprotective response to a pro-apoptotic response as demonstrated by the upregulation of CHOP and processing of pro-caspase-12. Thus, we provide evidence that the ER can generate and propagate apoptotic signals in response to ischemic stress and this pathway is therefore a novel target for prevention of ischemia-mediated cardiomyocyte loss.

Animals↗
PubMed2005

Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway.

In the broadest sense, cellular stress describes conditions wherein cells encounter and react to a 'non-normal' state. Perturbations may originate through both extracellular and intracellular means. Whereas transient levels of stress are expected to occur on a regular basis, a series of checks and balances ensures that cells are well equipped to maintain a homeostatic state. In the case of supra-physiological stress signaling, cellular challenges are more severe, and programmed cell death may be the best option for the organism. The ability of a cell, and by extension, an organism, to adequately manage cellular stress is fundamental--a question of life or death. The endoplasmic reticulum (ER) is exquisitely poised to sense and respond to cellular stresses including those that result from metabolic and/or protein folding imbalances. In response to stress originating from within the ER, the PERK and Ire1 protein kinases, along with other proximal signaling molecules, initiate a program of transcriptional and translational regulation termed the unfolded protein response. A consequence of ER stress is the accumulation of reactive oxygen species that promotes a state of oxidative stress. PERK signaling, via activation of the Nrf2 and ATF4 transcription factors, coordinates the convergence of ER stress with oxidative stress signaling. Here we discuss progress regarding the signaling pathways involved in these cellular stresses and the implications of the intersection between the two signaling pathways.

Activating Transcription Factor 6↗
PubMed2004

Prevention of endoplasmic reticulum stress-induced cell death by brain-derived neurotrophic factor in cultured cerebral cortical neurons.

Brain-derived neurotrophic factor (BDNF), one of the neurotrophic factors acting in the central nervous system (CNS), prevents ordinary types of neuronal cell death induced by various stimulants. On the other hand, an accumulation of unfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and then induces ER stress-mediated cell death. The ER stress-mediated cell death is distinctive because the caspase-12 activity plays a crucial role in the progression of cell death. We previously showed that nerve growth factor (NGF) attenuated ER stress-mediated cell death in non-neuronal PC12 cells. Here, we report that BDNF suppressed the ER stress-mediated cell death in tunicamycin (Tm)-treated cerebral cortical neurons. An analysis using a specific inhibitor of phosphatidylinositol 3-kinase (PI3-K), LY294002, revealed that BDNF prevented this cell death via the PI3-K signaling pathway. We found that the number of NeuN/TUNEL-double positive cells and the activity of caspase-3 suppressed by BDNF were increased by LY294002. We also discovered that LY294002 diminished the effect of BDNF on the activation of caspase-12, indicating that BDNF prevents ER stress-mediated cell death via a PI3-K-dependent mechanism by suppressing the activation of caspase-12 in cultured CNS neurons.

Analysis of Variance↗
PubMed2005

Endoplasmic reticulum Ca2+ depletion induces endothelial cell apoptosis independently of caspase-12.

OBJECTIVE: Apoptosis of endothelial cells is considered an initial step in the development of atherosclerosis. Recent studies have indicated that depletion of the endoplasmic reticulum (ER) Ca(2+) content plays an important role in apoptosis. Caspase-12 is a key signal in ER stress-induced apoptosis. However, it is not known whether the depletion of ER Ca(2+) is linked to caspase-12 signalling in endothelial cells. Here we have investigated the interaction of Ca(2+) signalling and caspase-12 cleavage in apoptosis of endothelial cells. METHODS: Cytosolic Ca(2+) concentration ([Ca(2+)](i)) of primary porcine aortic endothelial cells was measured using fura-2/AM. Apoptosis was assessed by DNA fragmentation, and cleavage of caspase-12 using Western blotting techniques. RESULTS: Thapsigargin (5 microM), an inhibitor of the ER Ca(2+)-ATPase, depleted ER Ca (2+) content, increased [Ca(2+)](i), cleaved caspase-12, and induced apoptosis. Bradykinin (10 nM) also increased [Ca(2+)](i) but did not cleave caspase-12 or induce apoptosis. However, when intracellular Ca(2+) was chelated with BAPTA/AM (100 microM), bradykinin caused ER Ca(2+) depletion and apoptosis without accompanying caspase-12 cleavage. A non-selective caspase inhibitor, z-VAD.fmk (100 microM), inhibited apoptosis and cleavage of caspase-12 stimulated by thapsigargin, while a calpain inhibitor, MDL 28170 (120 microM), inhibited caspase-12 cleavage but not apoptosis. CONCLUSIONS: Thus, increases in intracellular Ca(2+) concentration are not sufficient for the induction of apoptosis in endothelial cells, and ER Ca(2+) depletion appears to induce apoptosis independently of caspase-12.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Ischemic acidosis causes apoptosis in coronary endothelial cells through activation of caspase-12.

OBJECTIVE: Myocardial ischemia has been shown to induce apoptosis of endothelial cells (EC). However, the mechanism of this endothelial injury is still poorly understood. To analyse the signaling pathway of ischemia-induced EC apoptosis was the aim of the present study. METHODS: The primary culture of rat coronary EC was exposed to simulated ischemia (glucose-free anoxia at pH(o) 6.4). Apoptosis was defined by staining of nuclei with Hoechst-33342 and TUNEL. Cytosolic Ca2+ and pH were measured with Fura-2 and BCECF, respectively. RESULTS: Apoptosis (29.2+/-1.7% of cells) induced by exposure to simulated ischemia for 2 h was accompanied by cytosolic Ca2+ overload (1090+/-52 nmol/l) and acidosis (pHi = 6.52+/-0.13). Simulated ischemia had no significant effect on caspase-8 cleavage, but induced cleavage of caspase-3 and caspase-12 and led to a slight release of cytochrome C. Prevention of cytosolic acidosis (anoxia at pH(o) 7.4) had no effect on cytochrome C release, but significantly reduced apoptosis, attenuated cytosolic Ca2+ overload, and prevented cleavage of caspase-12. A similar effect was achieved by inhibition of Ca2+ release channels in the endoplasmic reticulum with ryanodine and xestospongin C. Knock-down of caspase-12 with small interfering RNA suppressed caspase-3 activation and reduced apoptotic cell number by about 70%. CONCLUSION: Acidosis, rather than anoxia, is an important trigger of apoptosis in EC under simulated ischemia. The main pathway of the simulated ischemia-induced apoptosis consists of the Ca2+ leak from the ER followed by activation of caspase-12 and caspase-3.

Acidosis↗
PubMed2005

Cypermethrin blocks a mitochondria-dependent apoptotic signal initiated by deficient N-linked glycosylation within the endoplasmic reticulum.

The endoplasmic reticulum (ER) serves as a critical site of protein synthesis and processing. The temperature-sensitive hamster fibroblast cell line (tsBN7) displays deficient N-linked glycosylation activity at the restrictive temperature and activates cellular apoptosis. Temperature-shifted tsBN7 cells display induction of Grp78 and Gadd153, genes known to be induced by ER stress, and activate apoptosis via the release of cytochrome c from the mitochondria. Cyclosporin A (CsA), a potent blocker of the mitochondrial permeability transition pore (PTP), was sufficient to block cytochrome c release and to rescue tsBN7 cells from apoptosis. CsA-treated cells displayed Grp78 induction at the restrictive temperature, consistent with an ER stress signal being carried to the nucleus, while the apoptosis-associated transcription factor, Gadd153, displayed only a mild induction. Cypermethrin, a type II pyrethroid known to perturb Ca(2+) signaling in neuronal cells, was sufficient to arrest apoptosis under these conditions. This work identifies type II pyrethroids as a valuable new tool in the characterization of cellular stress signaling pathways.

Animals↗
PubMed2006

Apoptotic effects of Antrodia cinnamomea fruiting bodies extract are mediated through calcium and calpain-dependent pathways in Hep 3B cells.

Antrodia cinnamomea is well known in Taiwan as a traditional medicine for treating cancer and inflammation. The purpose of this study was to evaluate the apoptotic effects of ethylacetate extract from A. cinnamomea (EAC) fruiting bodies in Hep 3B, a liver cancer cell line. EAC decreased cell proliferation of Hep 3B cells by inducing apoptotic cell death. EAC treatment increased the level of calcium (Ca2+) in the cytoplasm and triggered the subsequent activation of calpain and caspase-12. EAC also initiated the mitochondrial apoptotic pathway through regulation of Bcl-2 family proteins expression, release of cytochrome c, and activation of caspase-9 in Hep 3B cells. Furthermore, the mitochondrial apoptotic pathway amplified the calpain pathway by Bid and Bax interaction and Ca2+ translocation. We have therefore concluded that the molecular mechanisms during EAC-mediated proliferation inhibition in Hep 3B cells were due to: (1) apoptosis induction, (2) triggering of Ca2+/calpain pathway, (3) disruption of mitochondrial function, and (4) apoptotic signaling being amplified by cross-talk between the calpain/Bid/Bax and Ca2+/mitochondrial apoptotic pathways.

Apoptosis↗
PubMed2004

Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats.

We investigated in vivo the chemotherapeutic anthracycline agents doxorubicin and its ability to activate mitochondrial-mediated, receptor-mediated and endoplasmic/sarcoplasmic reticulum-mediated apoptosis transduction pathways in cardiac tissue from male and female rats. We administered a single low dose of doxorubicin (10 mg/kg of body weight, i.p.) and then isolated mitochondrial and cytosolic proteins one and four days later from the heart. Caspase-3 protein content and caspase-3 activity were significantly increased after day four of doxorubicin treatment in both male and female rats. However, while males had DNA fragmentation at day one but not day four following doxorubicin administration, females showed no significant increase in DNA fragmentation at either time. Caspase-12, localized in the SR, is considered a central caspase, and its activation by cleavage via calpain indicates activation of the SR-mediated pathway of apoptosis. Cleaved caspase-12 content and calpain activity significantly increased after day four of doxorubicin treatment in both sexes. In the mitochondrial-mediated pathway, there were no significant treatment effects observed in cytosolic cytochrome c and cleaved (active) caspase-9 in either sex. In control rats (saline injection), glutathione peroxidase (GPX) activity and hydrogen peroxide (H2O2) production were lower in females compared to males. Doxorubicin treatment did not significantly affect H2O2, GPX activity or ATP production in isolated mitochondria in either sex. Female rats produced significantly lower levels of H2O2 production one day after doxorubicin treatment, whereas male rats produced significantly less mitochondrial H2O2 four days after doxorubicin treatment. The receptor-mediated pathway (caspase-8 and c-FLIP) showed no evidence of being significantly activated by doxorubicin treatment. Hence, doxorubicin-induced apoptosis in vivo is mediated by the SR to a greater extent than other apoptotic pathways and should therefore be considered for targeted therapeutic interventions. Moreover, no major sex differences exist in apoptosis signaling transduction cascade due to doxorubicin treatment.

Animals↗
PubMed2005

Endoplasmic reticulum stress induced in motor neurons by transient spinal cord ischemia in rabbits.

OBJECTIVE: The mechanism of spinal cord injury has been thought to be related to the vulnerability of spinal motor neuron cells against ischemia. However, the mechanisms of such vulnerability are not fully understood. Because we previously reported that spinal motor neurons were probably lost as the result of programmed cell death, we investigated a possible mechanism of neuronal death by immunohistochemical analysis for Grp78 and caspase12. METHODS: We used a rabbit spinal cord ischemia model with a balloon catheter. The spinal cord was removed at 8 hours or 1, 2, or 7 days after 15 minutes of transient ischemia. Histologic changes were studied with hematoxylin-eosin staining. Western blot analysis for Grp78 and caspase12, temporal profiles of Grp78 and caspase12 immunoreactivity, and double-label fluorescence immunocytochemical studies were performed. RESULTS: The majority of motor neurons were preserved for 2 days but were selectively lost at 7 days of reperfusion. Western blot analysis revealed scarce immunoreactivity for Grp78 and caspase12 in the sham-operated spinal cords. However, immunoreactivity for Grp78 and caspase12 became apparent at 8 hours after transient ischemia, which returned to the baseline level at 1 day. Double-label fluorescence immunocytochemical study revealed that both Grp78 and caspase12 were positive at 8 hours of reperfusion in the same motor neurons that eventually die. CONCLUSION: This study demonstrated that immunoreactivities for both Grp78 and caspase12 were induced in the same motor neuron that eventually dies. These results suggest that endoplasmic reticulum stress was induced in motor neurons by transient spinal cord ischemia in rabbits.

Animals↗
PubMed2005

Clofibrate-induced apoptosis is mediated by Ca2+-dependent caspase-12 activation.

The mechanism of fibrate-induced myopathy was investigated in this report. When clofibrate (30 to 300 microM) was applied to L6 rat skeletal myoblasts, dose-dependently apoptosis was observed within 24 h. In the apoptotic myoblasts, a caspase-12 cleavage was observed at 2 h and with following caspases-9 and -3-related cascade activation. In contrast, the neutral protease calpain, that is a key enzyme in ER stress-related apoptosis via caspase-12 activation, was significantly decreased during apoptosis. Next, the authors evaluated a role of calcium-dependent signal(s). When clofibrate was added into medium, cytosolic calcium concentration was rapidly and persistently increased. On the other hand, an addition of 10 mM EGTA depressed sustained calcium phase, and concurrent myoblasts apoptosis was completely inhibited. Taken together, our findings indicate that the clofibrate-induced myopathy is triggered by Ca2+ influx, then activated cytosolic caspase-12 through calpain-independent cascade, and consequently caused apoptotic DNA fragmentation.

Animals↗
PubMed2006

Endoplasmic reticulum stress response is involved in the pathogenesis of stress induced gastric lesions in rats.

Stress gastric ulcer is a serious complication, but the mechanism involved is not fully clarified. It is well known that mucosal cell apoptosis plays a crucial role in the pathogenesis of gastric ulceration. Recent studies have shown that endoplasmic reticulum (ER) stress is an important pathway leading to cellular apoptosis. To investigate the role of ER stress in the pathogenesis of stress gastric ulcer, we studied the alteration in the expression of ER stress markers GRP78 (glucose-regulated protein 78) and caspase-12 (an ER stress-specific proapoptotic molecule) and their relations with gastric mucosal apoptosis during development of stress gastric lesions in the water-immersion and restraint stress (WRS) model in rats. Rats developed severe gastric lesions after 6 h of WRS. Typical apoptosis was observed at the edge cells of WRS induced gastric lesions. Western blot analysis showed that GRP78 and activated caspase-12 were over-expressed in the gastric tissues of WRS rats. Immunohistochemical analysis demonstrated that increased GRP78 and caspase-12 were distributed only under the lesions. In addition, dithiothreitol and tunicamycin (ER stress inducers), which increased the expression of GRP78 and activated caspase-12, caused gastric mucosal injury and mucosal cell apoptosis in vitro. These findings suggest that ER stress might be involved in the development of stress gastric ulcer through an apoptotic mechanism.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Hippocalcin protects against caspase-12-induced and age-dependent neuronal degeneration.

Hippocalcin is a neuronal calcium binding protein, but its physiological function in brain is unknown. We show here that hippocampal neurons from hippocalcin-deficient mice are more vulnerable to degeneration, particularly using thapsigargin, elevating intracellular calcium. Caspase-12 was activated in neurons lacking hippocalcin, while calpain was unchanged. Neuronal viability was accompanied by endoplasmic reticulum (ER) stress and a change in the relative induction of the ER chaperone, BiP/GRP78. Neuronal apoptosis inhibitor protein (NAIP), known to interact with hippocalcin, was not altered, but hippocampal neurons from gene-deleted mice were more sensitive to excitotoxicity caused by kainic acid. In addition, an age-dependent increase in neurodegeneration occurred in the gene-deleted mice, showing that hippocalcin contributes to neuronal viability during aging.

Aging↗
PubMed2004

Opposed regulation of aluminum-induced apoptosis by glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor in rat brains.

When intracisternally injected to rat brain, aluminum induced apoptosis as assessed by DNA fragmentation and activation of caspase-3 and caspase-12. Co-administration of glial cell line-derived neurotrophic factor (GDNF) effectively prevented aluminum-induced cell death through reduced apoptosis whereas brain-derived neurotrophic factor (BDNF) accelerated aluminum-induced apoptosis, suggesting that the extent of aluminum neurotoxicity in vivo may depend on the biological activity of the neurotrophic factors.

Animals↗
PubMed2004

GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis.

GM1-ganglioside (GM1) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of GM1 due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease GM1-gangliosidosis, but whether the accumulation of GM1 is directly responsible for CNS pathogenesis was unknown. Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of GM1-gangliosidosis. GM1 loading of wild-type neurospheres recapitulated the phenotype of beta-gal-/- cells and activated this pathway by depleting ER calcium stores, which ultimately culminated in apoptosis. Activation of UPR pathways did not occur in mice double deficient for beta-gal and ganglioside synthase, beta-gal-/-/GalNAcT-/-, which do not accumulate GM1. These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid GM1 and this causes a novel mechanism of neuronal apoptosis.

Animals↗
PubMed2006

Induced endoplasmic reticulum (ER) stress and binding of over-expressed ER specific chaperone GRP78/BiP with dimerized epidermal growth factor receptor in mammalian cells exposed to low concentration of N-methyl-N'-nitro-N-nitrosoguanidine.

Previously we have shown that alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) can induce the clustering of epidermal growth factor receptor (EGFR) in human amnion FL cells. However, the biological consequence of MNNG-induced clustering is different from that of epidermal growth factor (EGF)-induced clustering. In addition, MNNG strongly blocks the autophosphorylation of EGFR in response to its ligand, we speculate it might be due to the altered conformation of EGFR by MNNG alkylation, or the binding of some unknown suppressive molecules to EGFR, which could lead to the down-regulation of EGFR pathway. In this study, we further demonstrated that EGFR could not be phosphorylated by EGF in lysates prepared from MNNG-pretreated cell. In addition, it was found that the clustering of EGFR induced by low concentration (<or=1 microM) of MNNG on cell surface was indeed the dimerization of EGFR; however, unlike EGF treatment, the dimerization initiated by MNNG was irreversible upon mild-acid washing. Besides, in accordance with our previous results, the recruitment of adaptor proteins Grb-2/Sos1, which play key roles in activating ensuing RAS-MAPK pathway, was also suppressed. Interestingly, we found that endoplasmic reticulum (ER) stress participates in MNNG-induced down-regulation of EGFR signaling. It was demonstrated that the ER specific chaperone, glucose-regulated protein 78 (GRP78/BiP) formed a stable complex with EGFR in MNNG-treated cell. However, in the presence of 1mM ATP, EGF induced phosphorylation of tyrosine residues of EGFR can be revitalized in lysates prepared from MNNG pretreated cells. We also found that MNNG can induce ER stress or unfolded protein response (UPR) which is characterized by induced expression of ER-stress response proteins, such as GRP78/BiP, GADD153/CHOP, and activation of ER-localized caspase-12. Therefore, it is concluded MNNG is also an ER stress inducer. In MNNG-exposed cells, ER stress plays an important role in the blockage of EGFR-signaling pathway by forming a stable complex of EGFR/BiP.

Amnion↗
PubMed2004

Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12.

Recently, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal death in patients with Alzheimer's disease. Treatment of human neuroblastoma cells with ER stress inducers causes apoptotic death. We confirmed that ER stress inducers specifically targeted the ER to cause apoptotic morphological changes. We also found that caspase-3, and not caspase-9 (a known mitochondrial apoptotic mediator), was mainly activated by ER stress. We generated the neuroblastoma cells that stably expressed caspase-12 and analyzed its influence on caspase-3 activation and vulnerability to ER stress. Cells expressing caspase-12 were more vulnerable to ER stress than cells expressing the empty vector, concomitant with increased activation of caspase-3. These findings suggested that activation of ER-resident caspase-12 indirectly activates cytoplasmic caspase-3 and might be important in ER stress-induced neuronal apoptosis.

Apoptosis↗
PubMed2006

Thiamine deficiency induces endoplasmic reticulum stress in neurons.

Thiamine (vitamin B1) deficiency (TD) causes region selective neuronal loss in the brain; it has been used to model neurodegeneration that accompanies mild impairment of oxidative metabolism. The mechanisms for TD-induced neurodegeneration remain incompletely elucidated. Inhibition of protein glycosylation, perturbation of calcium homeostasis and reduction of disulfide bonds provoke the accumulation of unfolded proteins in the endoplasmic reticulum (ER), and cause ER stress. Recently, ER stress has been implicated in a number of neurodegenerative models. We demonstrated here that TD up-regulated several markers of ER stress, such as glucose-regulated protein (GRP) 78, growth arrest and DNA-damage inducible protein or C/EBP-homologus protein (GADD153/Chop), phosphorylation of eIF2alpha and cleavage of caspase-12 in the cerebellum and the thalamus of mice. Furthermore, ultrastructural analysis by electron microscopic study revealed an abnormality in ER structure. To establish an in vitro model of TD in neurons, we treated cultured cerebellar granule neurons (CGNs) with amprolium, a potent inhibitor of thiamine transport. Exposure to amprolium caused apoptosis and the generation of reactive oxygen species in CGNs. Similar to the observation in vivo, TD up-regulated markers for ER stress. Treatment of a selective inhibitor of caspase-12 significantly alleviated amprolium-induced death of CGNs. Thus, ER stress may play a role in TD-induced brain damage.

Amprolium↗
PubMed2005

Tula hantavirus triggers pro-apoptotic signals of ER stress in Vero E6 cells.

Tula virus is a member of the Hantavirus genus of the family Bunyaviridae. Viruses of this family have an unusual pattern of intracellular maturation at the ER-Golgi compartment. We recently found that Tula virus, similar to several other hantaviruses, is able to induce apoptosis in cultured cells [Li, X.D., Kukkonen, S., Vapalahti, O., Plyusnin, A., Lankinen, H., Vaheri, A., 2004. Tula hantavirus infection of Vero E6 cells induces apoptosis involving caspase 8 activation. J. Gen. Virol. 85, 3261-3268.]. However, the cellular mechanisms remain to be clarified. In this study, we demonstrate that the progressive replication of Tula virus in Vero E6 cells initiates several death programs that are intimately associated with ER stress: (1) early activation of ER-resident caspase-12; (2) phosphorylation of Jun NH2-terminal kinase (JNK) and its downstream target transcriptional factor, c-jun; (3) induction of the pro-apoptotic transcriptional factor, growth arrest- and DNA damage-inducible gene 153, or C/EBP homologous protein (Gadd153/chop); and (4) changes in the ER-membrane protein BAP31 implying cross-talk with the mitochondrial apoptosis pathway. Furthermore, we confirmed that a sustained ER stress was induced marked by an increased expression of an ER chaperone Grp78/BiP. Taken together, we have identified involvement of ER stress-mediated death program in Tula virus-infected Vero E6 cells which provides a new approach to understand the mechanisms in hantavirus-induced apoptosis.

Animals↗