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)

The cAMP signaling pathway plays an essential role in modulating the apoptotic response to various stress stimuli. Until now, it was attributed exclusively to the activity of the G-protein-responsive transmembrane adenylyl cyclase. In addition to transmembrane AC, mammalian cells possess a second source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC). However, the role of this cyclase in apoptosis was unknown. A mitochondrial localization of this cyclase has recently been demonstrated, which led us to the hypothesis that sAC may play a role in apoptosis through modulation of mitochondria-dependent apoptosis. To prove this hypothesis, apoptosis was induced by simulated in vitro ischemia or by acidosis, which is an important component of ischemia. Suppression of sAC activity with the selective inhibitor KH7 or sAC knockdown by small interfering RNA transfection abolished endothelial apoptosis. Furthermore, pharmacological inhibition or knockdown of protein kinase A, an important cAMP target, demonstrated a significant anti-apoptotic effect. Analysis of the underlying mechanisms revealed (i) the translocation of sAC to mitochondria under acidic stress and (ii) activation of the mitochondrial pathway of apoptosis, i.e. cytochrome c release and caspase-9 cleavage. sAC inhibition or knockdown abolished the activation of the mitochondrial pathway of apoptosis. Analysis of mitochondrial co-localization of Bcl-2 family proteins demonstrated sAC- and protein kinase A-dependent translocation of Bax to mitochondria. Taken together, these results suggest the important role of sAC in modulating the mitochondria-dependent pathway of apoptosis in endothelial cells.
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PMID:Soluble adenylyl cyclase controls mitochondria-dependent apoptosis in coronary endothelial cells. 1933 6

TNF-alpha has been reported to be relevant in stroke-induced neuronal death. However the precise function of TNF-alpha in brain ischemia remains controversial since there are data supporting either a detrimental or a protective effect. Here we show that TNF-alpha is released after oxygen-glucose deprivation (OGD) of cortical cultures and is a major contributor to the apoptotic death observed without affecting the OGD-mediated necrotic cell death. In this paradigm, apoptosis depends on TNF-alpha-induced activation of caspase-8 and -3 without affecting the activation of caspase-9. By using knock-out mice for TNF-alpha receptor 1, we show that the activation of both caspase-3 and -8 by TNF-alpha is mediated by TNF-alpha receptor 1. The pro-apoptotic role of TNF-alpha in OGD is restricted to neurons and microglia, since astrocytes do not express either TNF-alpha or TNF-alpha receptor 1. Altogether, these results show that apoptosis of cortical neurons after OGD is mediated by TNF-alpha/TNF-alpha receptor 1.
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PMID:Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. 1955 59

The present study was designed to investigate the cardio-protective effect of Ac-LEDH-cmk a selective caspase-9 inhibitor and 5-aminoisoquinolinone a selective Poly (ADP-ribose) polymerase inhibitor on ischemia and reperfusion induced apoptotic and necrotic cell death in rats. Isolated rat hearts were exposed to 30 minutes of global ischemia followed by 120 minutes of reperfusion using Langendorff's apparatus. Myocardial injury was assessed in the terms of infarct size, release of lactate dehydrogenase, creatine kinase enzymes and apoptotic index was assessed by DNA smearing on agarose gel electrophoresis. Pretreatments with specific inhibitor of caspase-9, Ac-LEHD-cmk (0.07 muM and 0.105 muM), and inhibitor of PARP, 5-aminoisoquinolinone (5 microM and 7.5 muM), significantly attenuated I/R induced increase in infarct size, release of lactate dehydrogenase and creatine kinase in the coronary effluent, and apoptotic index. Therefore, it may be concluded that inhibition of caspase-9 and PARP prevent ischemia and reperfusion-induced activation of apoptotic cascade and necrosis in rat myocardium.
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PMID:Protective effects of caspase-9 and poly(ADP-ribose) polymerase inhibitors on ischemia-reperfusion-induced myocardial injury. 1964 85

Pressure ulcer is a complex and significant health problem. Although the factors including pressure, shear, and ischemia have been identified in the etiology of pressure ulcer, the cellular and molecular mechanisms that contribute to the development of pressure ulcer are unclear. This study tested the hypothesis that the early-onset molecular regulation of pressure ulcer involves apoptosis in muscle tissue. Adult Sprague-Dawley rats were subjected to an in vivo protocol to mimic pressure-induced deep tissue injury. Static pressure was applied to the tibialis region of the right limb of the rats for 6 h each day on two consecutive days. The compression force was continuously monitored by a three-axial force transducer equipped in the compression indentor. The contralateral uncompressed limb served as intra-animal control. Tissues underneath the compressed region were collected for histological analysis, terminal dUTP nick-end labeling (TUNEL), cell death ELISA, immunocytochemical staining, and real-time RT-PCR gene expression analysis. The compressed muscle tissue generally demonstrated degenerative characteristics. TUNEL/dystrophin labeling showed a significant increase in the apoptotic muscle-related nuclei, and cell death ELISA demonstrated a threefold elevation of apoptotic DNA fragmentation in the compressed muscle tissue relative to control. Positive immunoreactivities of cleaved caspase-3, Bax, and Bcl-2 were evident in compressed muscle. The mRNA contents of Bax, caspase-3, caspase-8, and caspase-9 were found to be higher in the compressed muscle tissue than control. These results demonstrated that apoptosis is activated in muscle tissue following prolonged moderate compression. The data are consistent with the hypothesis that muscle apoptosis is involved in the underlying mechanism of pressure-induced deep tissue injury.
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PMID:Muscle apoptosis is induced in pressure-induced deep tissue injury. 1964 27

Hippocampal dentate gyrus possesses an exceptional capacity of adaptation to ischemic insults. Recently, using a transient global ischemic model in the adult rat, we identified a neuroprotective signalling cascade in the dentate gyrus involving calcium/calmodulin-dependent protein kinase IV (CaMKIV), cyclic AMP response element (CRE)-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), a major regulator of survival. We have shown that intracerebroventricular injections of anti-BDNF and anti-CREB are sufficient to cause substantial tissular damages and apoptotic deaths in late periods (48-72 h) after ischemia. Herein, we provide immunohistochemical and biochemical evidence that antibody-induced impairment of the protective CaMKIV/CREB/BDNF pathway induces an apparent duality of response in the dentate gyrus. The experimental protocol is performed as follows: (a) rats are anesthetized and vertebral arteries are occluded by electrocauterization; (b) on the following day, transient global ischemia is produced by occlusion of carotid arteries for 25 min; (c) finally, rats are infused with the pharmacologic agents into the left cerebral ventricle and then perfusion-fixed at different time points after ischemia for immunohistochemical and immunoblotting analyses. After infusion with anti-CaMKIV, phosphorylation of mitogen-activated protein kinases (MAPK) MKK3, MKK6 and p38 and phospho-acetylation of histone H3 occur at 6 h after ischemia without presence of any caspase-9 activation and cellular injuries. In contrast, infusion of anti-BDNF or anti-CREB surprisingly results in a remarkable stimulation of casein kinase 2 (CK2) and caspase-9 activities at 48-72 h post-insult. This is accompanied by the disappearance of phosphorylation of MKK(3/6) and p38 and phospho-acetylation of histone H3. These results suggest that: (1) activation of a MKK(3/6)/p38/H3 cascade at early periods post-ischemia may be capable of causing a short transient protective effect in the dentate gyrus; (2) CK2 might be implicated in inhibition of activity of molecules such as MKK(3/6), p38 and deacetylases at late periods post-insult, thereby promoting injuries and cell deaths in the dentate cell layer.
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PMID:Temporal assessment of histone H3 phospho-acetylation and casein kinase 2 activation in dentate gyrus from ischemic rats. 1976 64

Hydrogen sulfide (H2S) displays anti-inflammatory and cytoprotective activities as evidenced by the inhibition of myocardial ischemia-reperfusion injury and production of lipid peroxidation. H2S also exerts many physiological or pathological effects on livers. Therefore, we designed the present study to investigate the roles of H2S in hepatic ischemia-reperfusion (HIR)-induced injury in rats by measuring H2S levels, H2S synthesizing activity, and cystathionine gamma-lyase (CSE) messenger RNA (mRNA) expression. We also applied DL-propargyl glycine (PAG) and sodium hydrosulfide (NaHS) to investigate their effects on the severity of liver injury induced by HIR. The levels of H2S, H2S production activity, and CSE mRNA expression in livers were increased by HIR. Administration of NaHS significantly attenuated the severity of liver injury and inhibited the production of lipid peroxidation, serum inflammatory factors [including nitric oxide, tumor necrosis factor alpha (TNF-alpha), interleukin 10, and intercellular cell adhesion molecule 1], cell apoptosis, and apoptosis-related proteins (including caspase-3, Fas, Fas ligand, and TNF-alpha), which were caused or elevated by HIR, whereas PAG aggravated them. However, NaHS or PAG did not show significant effects on the activation of caspase-9, which was also increased by HIR. Although further investigation is required, this study may indicate that H2S plays a protective role in HIR-induced injury.
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PMID:Role of hydrogen sulfide in hepatic ischemia-reperfusion-induced injury in rats. 1979 Jan 58

In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemia-reperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.
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PMID:Dexamethasone ameliorates renal ischemia-reperfusion injury. 1979 68

The release of cytochrome c from the mitochondria to the cytosol is a critical step for downstream caspase-mediated apoptotic signal transduction in ischemia-reperfusion (I/R)-induced myocardial tissue injury. 10-N-nonyl acridine orange (NAO), a cardiolipin-specific dye, has been shown to inhibit Bid-mediated cytochrome c release from isolated mitochondria in vitro; however, the possible protective effects of NAO and the mechanisms underlying the protection from myocardial I/R-induced tissue injury in a rat model are unknown. Male Sprague-Dawley rats were subjected to a 30-min coronary arterial occlusion followed by reperfusion. All rats received either vehicle or NAO (100 microg/kg iv) 10 min before the occlusion. The infarct size in the heart at 24 h after reperfusion was significantly reduced in NAO-treated rats compared with vehicle-treated rats. NAO treatment significantly reduced the cytosolic cytochrome c contents and caspase-9 activity in the ischemic region but did not affect caspase-8 activity. Furthermore, NAO treatment markedly suppressed the translocation of truncated Bid, a proapoptotic Bcl-2 family member, to the mitochondrial fraction. NAO also suppressed the mitochondrial swelling and oxygen uptake stimulated by calcium overload. The results suggest that NAO possesses protective effects against myocardial I/R injury, which may be due to the suppression of cytochrome c release through blockade of truncated Bid translocation to mitochondria and inhibition of the opening of mitochondrial permeability transition pores.
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PMID:Inhibition of cytochrome c release by 10-N-nonyl acridine orange, a cardiolipin-specific dye, during myocardial ischemia-reperfusion in the rat. 1994 77

The effects of citicoline used either alone or in combination with hypothermia on the suppression of apoptotic processes after transient focal cerebral ischemia were investigated. Middle cerebral artery occlusion (MCAo) was performed for 2 hours on Sprague-Dawley (SD) rats using intraluminal thread insertion. The treatment groups were as follows: Group 1, sham-operated; Group 2, saline; Group 3, citicoline (400mg/kg intraperitoneal.); Group 4, hypothermia (34+/-1 degrees C); Group 5, citicoline+hypothermia. All rats were reperfused for 24 hours, and after sacrifice and transcardiac perfusion, immunohistochemical studies were performed for markers of apoptosis. In Group 2, the Bcl-2 immunostaining score (mean+/-standard deviation, 0.71+/-0.75) was lower compared to Groups 3, 4 and 5 (2.33+/-0.81; 3.00+/-0.00; 2.20+/-0.83; p<0.05). There was higher expression of caspase-3 proteins in Group 2 (2.28+/-0.95) compared to Group 5 (1.50+/-0.83; p<0.05). Bax proteins were also increased in Group 2 (1.85+/-1.06) compared to Group 5 (0.40+/-0.54) and in Group 4 (2.00+/-0.00) compared to Group 5 (0.40+/-0.54; p<0.05). Significant differences in caspase-9 immunostaining scores were found in Group 2 (2.29+/-0.96) compared to Group 5 (0.20+/-0.44) (p<0.05); Group 3 (1.00+/-0.70) compared to Group 5 (0.20+/-0.44; p<0.05); and Group 4 (3.00+/-0.00; p<0.05) compared to Group 5 (0.40+/-0.54; p<0.05). Thus by suppressing apoptotic processes citicoline with hypothermia is more effective than either used alone in ameliorating cerebral damage after transient focal ischemia.
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PMID:Effects of citicoline used alone and in combination with mild hypothermia on apoptosis induced by focal cerebral ischemia in rats. 2003 28

Acetaminophen, a popular analgesic and antipyretic, has been found to be effective against neuronal cell death in in vivo and in vitro models of neurological disorders. Acute neuronal death has been attributed to loss of mitochondrial permeability transition coupled with mitochondrial dysfunction. The potential impact of acetaminophen on acute injury from cerebral ischemia-reperfusion has not been studied. We investigated the effects of acetaminophen on cerebral ischemia-reperfusion-induced injury using a transient global forebrain ischemia model. Male Sprague-Dawley rats received 15mg/kg of acetaminophen intravenously during ischemia induced by hypovolemic hypotension and bilateral common carotid arterial occlusion, which was followed by reperfusion. Acetaminophen reduced tissue damage, degree of mitochondrial swelling, and loss of mitochondrial membrane potential. Acetaminophen maintained mitochondrial cytochrome c content and reduced activation of caspase-9 and incidence of apoptosis. Our data show that acetaminophen reduces apoptosis via a mitochondrial-mediated mechanism in an in vivo model of cerebral ischemia-reperfusion. These findings suggest a novel role for acetaminophen as a potential stroke therapeutic.
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PMID:Acetaminophen reduces mitochondrial dysfunction during early cerebral postischemic reperfusion in rats. 2007 45


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