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)

We have performed differential screening to identify genes participating in NMDA-induced neuronal death. The gas1 (growth arrest-specific gene 1) gene, whose product is known to inhibit cell cycle progression, was induced in cultured corticohippocampal neurons committed to die after a brief exposure to NMDA. Overexpression of Gas1 in cultured hippocampal neurons and in human neuroblastoma NB69 cells produced a marked reduction in the number of viable cells. Furthermore, gas1 antisense oligodeoxynucleotide or antisense mRNA protected hippocampal neurons or NB69 cells from neuronal death. Importantly, Gas1-induced neuronal death was attenuated by coexpression of the human Bcl-2 protein or the baculoviral caspase inhibitor OpIAP2. While Gas1 does not directly interact with Bcl-2, OpIAP2 coimmunoprecipitates with Gas1. In addition, induction of gas1 also occurred in rat brain in two models of excitotoxicity: delayed neuronal death after intraperitoneal kainate injection and neuronal death in hippocampal slices after ischemia. These results indicate that Gas1 is induced by activation of glutamate receptors and is part of the gene expression program directing neuronal death after mild excitotoxic insults.
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PMID:Gas1 is induced during and participates in excitotoxic neuronal death. 1190 13

This study shows the preventive effect of KR-31378 [(2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine] against cerebral infarct via antioxidant and antiapoptotic actions evoked by subjecting rats to 2 h of occlusion of the left middle cerebral artery followed by 24 h of reperfusion. The brain infarct zone in the cortex and striatum of the left hemisphere was consistently identified in the cortex and striatum of the left hemisphere. The infarct area was significantly reduced after three intraperitoneal administrations of 10, 30, or 50 mg/kg KR-31378 at 5 min, 4 h, and 8 h after the completion of 2 h of ischemia. Treatment with KR-31378 (30 or 50 mg/kg) significantly reduced the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells as well as strongly suppressed the laddered feature of DNA fragmentation in the lateral cortical tissue corresponding to the penumbra. The findings of samples from penumbral zone, which showed markedly reduced Bcl-2 protein level and increased Bax protein and cytochrome c release, were wholly reversed by treatment with KR-31378. In conclusion, postischemic treatment with KR-31378 provided significant levels of cortical neuroprotection in association with inhibition of apoptotic cell death through the up-regulation of Bcl-2 expression, and the down-regulation of Bax protein and cytochrome c release.
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PMID:Neuroprotective effect of (2S,3S,4R)-N"-cyano-N-(6-amino-3, 4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378), a benzopyran analog, against focal ischemic brain damage in rats. 1190 75

The effects of ischemia-reperfusion (IR) and ischemic preconditioning (IP) on hemodynamics, epicardial electrography, myocardial infarct size, cardiomyocytic apoptosis and gene proteins involving apoptosis (Fas, Bcl-2 and Bax) were observed in aneasthetized rabbit myocardium. The results are as follows. (1) During ischemia-reperfusion, heart rate, arterial blood pressure and myocardial oxygen consumption were reduced progressively. The epicardial electrographic ST-segment was elevated significantly during ischemia (P<0.001)and recovered to the baseline during reperfusion. (2) The infarct size occupied 57.7+/-2.0% of the ischemic myocardium in IR group while IP reduced the infarct size to 27.7+/-1.5% (P<0.01). (3) DNA ladder pattern of ischemic myocardium was revealed by agrose gel electrophoresis in IR group while it was not found in IP group. Apoptotic cardiomyocytes were sparse within the ischemic myocardium at risk in IP as compared with those in IR heart. Apoptosis rate of the ischemic myocardium from IR and IP groups detected by flow cytometry was 11.2+/-0.4% and 6.35+/-0.2% (P<0.01), respectively. (4) Fas and Bax protein expression in the ischemic myocardium of IR and IP groups was elevated as compared with those in non-ischemic myocardium group (P<0.05). The Fas protein expression of IR group was higher than that of IP group (P<0.05). Bcl-2/Bax ratio of IR group was lower than that in non-ischemic myocardium (P<0.01). From the results, it is suggested that IP decreases cardiomyocytic apoptosis induced by IR and this action is mediated by the reduction of Fas protein expression.
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PMID:[Ischemic preconditioning reduces cardiomyocytic apoptosis in rabbit heart in vivo]. 1195 68

Acute cerebral ischemia causes hypoxic neuronal cell death by necrosis and apoptosis. Expression of anti-apoptotic transgenes in ischemic brain may provide a useful therapeutic strategy for alleviation of postischemic damage. The present study investigates liposome-mediated transfer of the human bcl-2 protein in a rat model of focal transient ischemia due to middle cerebral artery (MCA) occlusion. Two different types of plasmid vectors were used for bcl-2 expression: one driven by the constitutive cytomegalovirus promoter (pCMV) and another based on the hypoxia-inducible human vascular endothelial growth factor promoter (pHRE). Cationic liposome/plasmid DNA complexes (lipoplexes) were injected directly into the cerebrospinal fluid (CSF) of rats immediately after MCA occlusion. The brains of treated and control animals were analyzed 48 h later. Infarct volumes and numbers of apoptotic cells were quantified. Occlusion of the MCA resulted in ipsilateral cerebral infarcts in all study animals. Transfer of the bcl-2 gene resulted in high level widespread protein expression in the case of the pCMV-bcl2 plasmid, while animals treated with the pHRE-bcl2 vector showed lower expression levels of bcl2 which were in addition limited to the ischemic area. Treatment with pCMV-bcl2, but not with pHRE-bcl2, was able to significantly reduce the infarct volume, which was 109 +/- 8 mm(3) for pCMV-bcl2, 152 +/- 29 mm(3) for pHRE-bcl2, and 155 +/- 18 mm(3) for control animals. Animals transfected with either vector showed a significant reduction in numbers of apoptotic cells in the infarct and penumbra area compared with controls. There were no short-term neurological side-effects of the CSF injection of lipoplexes or of bcl-2 expression. In conclusion, the hypoxia-inducible bcl-2 expression mediated by intrathecal lipoplexes may represent a novel, biologically safe and lesion-selective therapeutic approach for neuroprotection after acute cerebral ischemia. DOI: 10.1038/sj/gt/3301676
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PMID:Liposome-mediated transfer of the bcl-2 gene results in neuroprotection after in vivo transient focal cerebral ischemia in an animal model. 1196 Mar 18

Hypothermia improves resistance to ischemia in the cardioplegia-arrested heart. This adaptive process produces changes in specific signaling pathways for mitochondrial proteins and heat-shock response. To further test for hypothermic modulation of other signaling pathways such as apoptosis, we used various molecular techniques, including cDNA arrays. Isolated rabbit hearts were perfused and exposed to ischemic cardioplegic arrest for 2 h at 34 degrees C [ischemic group (I); n = 13] or at 30 degrees C before and during ischemia [hypothermic group (H); n = 12]. Developed pressure, the maximum first derivative of left ventricular pressure, oxygen consumption, and pressure-rate product (P < 0.05) recovery were superior in H compared with in I during reperfusion. mRNA expression for the mitochondrial proteins, adenine translocase and the beta-subunit of F1-ATPase, was preserved by hypothermia. cDNA arrays revealed that ischemia altered expression of 13 genes. Hypothermia modified this response to ischemia for eight genes, six related to apoptosis. A marked, near fivefold increase in transformation-related protein 53 in I was virtually abrogated in H. Hypothermia also increased expression for the anti-apoptotic Bcl-2 homologue Bcl-x relative to I but decreased expression for the proapoptotic Bcl-2 homologue bak. These data imply that hypothermia modifies signaling pathways for apoptosis and suggest possible mechanisms for hypothermia-induced myocardial protection.
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PMID:Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis. 1196 Sep 75

L-Glutamine (Gln) is known to have protective effect on the small intestine under deleterious stressful condition. Although the mechanism by which Gln confers intestinal cellular protection remains unclear, its potential role may be mediated via signal transduction including stress response genes and anti-apoptotic genes. Herein, we examined a possible role of stress response genes in warm ischemically injured small intestines. We measured mRNA and protein expression of heme oxygenase (HO)-1, Bcl-2 and Bax at different time points after Gln administration. Warm ischemia model was made by clamping of the superior mesenteric artery for 60 min. After reperfusion, tissue samples were taken for end labeling of nuclear DNA fragments (TdT-mediated d-uridine triphosphate biotin nick end labeling; TUNEL) and hematoxylin-eosin staining. In Gln-treated group, the substantial expression of HO-1 mRNA peaked at 3 h and reduced thereafter, while HO-1 protein synthesis was noted within 3 h and reached plateau thereafter. NO-1-positive components were markedly detected in the villus epithelial cells and crypts. The ratios of Bcl-2/Bax mRNA expression after Gln administration peaked at 3 h and reduced thereafter until 24 h. Bcl-2 immunoreactive protein was enhanced in Gln group, whereas Bax was faintly detected. Following reperfusion, less TUNEL-positive staining of the top of the villi and more prompt recovery of denuded villus epithelial cells were noted in Gln group, compared with those in untreated and lactated Ringer-treated control groups. In conclusion, a concomitant expression of anti-oxidative HO-1 and anti-apoptotic Bcl-2 molecules induced by non-toxic amino acid, Gln, may alleviate or even prevent intestinal warm ischemia and reperfusion injury, attenuating programmed cell death and promoting its reepithelialization.
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PMID:[Impact of stress response genes induced by L-glutamine on warm ischemia and reperfusion injury in the rat small intestine]. 1196 53

Despite the characterization of neuroprotection by transforming growth factor-beta1 (TGF-beta1), the signaling pathway mediating its protective effect is unclear. Bad is a proapoptotic member of the Bcl-2 family and is inactivated on phosphorylation via mitogen-activated protein kinase (MAPK). This study attempted to address whether MAPK signaling and Bad phosphorylation were influenced by TGF-beta1 and, furthermore, whether these two events were involved in the antiapoptotic effect of TGF-beta1. We found a gradual activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and MAPK-activated protein kinase-1 (also called Rsk1) and a concomitant increase in Bad phosphorylation at Ser(112) in mouse brains after adenovirus-mediated TGF-beta1 transduction under nonischemic and ischemic conditions induced by transient middle cerebral artery occlusion. Consistent with these effects, the ischemia-induced increase in Bad protein level and caspase-3 activation were suppressed in TGF-beta1-transduced brain. Consequently, DNA fragmentation, ischemic lesions, and neurological deficiency were significantly reduced. In cultured rat hippocampal cells, TGF-beta1 inhibited the increase in Bad expression caused by staurosporine. TGF-beta1 concentration- and time-dependently activated Erk1/2 and Rsk1 accompanied by an increase in Bad phosphorylation. These effects were blocked by U0126, a mitogen-activated protein kinase/Erk kinase 1/2 inhibitor, suggesting an association between Bad phosphorylation and MAPK activation. Notably, U0126 and a Rsk1 inhibitor (Ro318220) abolished the neuroprotective activity of TGF-beta1 in staurosporine-induced apoptosis, indicating that activation of MAPK is necessary for the antiapoptotic effect of TGF-beta1 in cultured hippocampal cells. Together, we demonstrate that TGF-beta1 suppresses Bad expression under lesion conditions, increases Bad phosphorylation, and activates the MAPK/Erk pathway, which may contribute to its neuroprotective activity.
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PMID:Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. 1201 9

It has been reported that apoptosis is a significant contributor to myocardial cell death as a result of reperfusion injury. However, whether the extent of cardiomyocyte apoptosis following ischemia and reperfusion varies in different pathophysiological backgrounds is still uncertain. In this study, we examined whether hypercholesterolemia increases the extent of myocardial reperfusion injury by aggravating cardiomyocyte apoptosis and the effects of hypercholesterolemia on the expression of Bcl-2 and Bax proteins and the activation of caspase-3. Twenty-eight male New Zealand white rabbits were fed standard chow (control, n = 14) or chow supplemented with 10% cholesterol (hypercholesterolemic, n = 14) for 8 wk. Anesthetized rabbits were then subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. Apoptosis was identified as "DNA ladders" by gel electrophoresis and confirmed histologically using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The infarct size (% of risk region) was significantly greater in hypercholesterolemic rabbits than in controls (39 +/- 6 vs. 23 +/- 2%, P = 0.02). Very few TUNEL-positive cardiomyocytes could be identified in the nonischemic regions in both groups, consistent with an absence of DNA laddering. In contrast, TUNEL-positive cardiomyocytes were significantly displayed in the ischemic, nonnecrotic myocardium, and DNA ladder occurred in all animals. The percentage of TUNEL-positive cardiomyocytes in the ischemic nonnecrotic myocardium was significantly higher in hypercholesterolemic rabbits compared with controls (40 +/- 5 vs. 17 +/- 11%, P < 0.001). Western blot analysis showed that, in the nonischemic myocardium, hypercholesterolemic rabbits exhibited an approximately 50% increase in the expression of Bcl-2 (P < 0.05), but not Bax, than control rabbits. However, compared with controls, hypercholesterolemic rabbits exhibited a more pronounced decrease in the expression of Bcl-2 (42 +/- 4 vs. 26 +/- 2%, P < 0.01) and a similar extent of increase in the expression of Bax in the ischemic myocardium. Furthermore, hypercholesterolemic rabbits were associated with a markedly increased activation of caspase-3 within the ischemic myocardium compared to control rabbits. This study demonstrates that although hypercholesterolemia is associated with an increased myocardial Bcl-2/Bax ratio at baseline, it still significantly exacerbates cardiac reperfusion injury, not only by increasing the infarct size but also by increasing the extent of cardiomyocyte apoptosis.
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PMID:Increased cardiomyocyte apoptosis following ischemia and reperfusion in diet-induced hypercholesterolemia: relation to Bcl-2 and Bax proteins and caspase-3 activity. 1203 Mar 19

This study examined the potential role of angiotensin type 2 (AT(2)) receptor on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by femoral artery ligature in both wild-type and AT(2) gene-deleted mice (Agtr2(-)/Y). After 28 days, angiogenesis was quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. Protein levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), Bax, and Bcl-2 were determined by Western blot analysis in hindlimbs. The AT(2) mRNA level (assessed by semiquantitative RT-PCR) was increased in the ischemic hindlimb of wild-type mice. Angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio, 1.9- and 1.7-fold, respectively, in Agtr2(-)/Y mice compared with controls. In ischemic leg of Agtr2(-)/Y mice, revascularization was associated with an increase in the antiapoptotic protein content, Bcl-2 (211% of basal), and a decrease (60% of basal) in the number of cell death, determined by TUNEL method. Angiotensin II treatment (0.3 mg/kg per day) raised angiogenic score, blood perfusion, and both VEGF and eNOS protein content in ischemic leg of wild-type control but did not modulate the enhanced angiogenic response observed in untreated Agtr2(-)/Y mice. Finally, immunohistochemistry analysis revealed that VEGF was mainly localized to myocyte, whereas eNOS-positive staining was mainly observed in the capillary of ischemic leg of both wild-type and AT(2)-deficient mice. This study demonstrates for the first time that the AT(2) receptor subtype may negatively modulate ischemia-induced angiogenesis through an activation of the apoptotic process.
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PMID:Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. 1203 96

Studies of ischemia/reperfusion (I/R) injury and preconditioning have shown that ion homeostasis, particularly calcium homeostasis, is critical to limiting tissue damage. However, the relationship between ion homeostasis and specific cell death pathways has not been investigated in the context of I/R. Previously we reported that calpain cleaved Bid in the absence of detectable caspase activation (1). In this study, we have shown that an inhibitor of the sodium/hydrogen exchanger prevented calpain activation after I/R. Calpain inhibitors prevented cleavage of Bid as well as the downstream indices of cell death, including DNA strand breaks, creatine kinase (CK) release, and infarction measured by triphenyl tetrazolium chloride (TTC) staining. In contrast, the broad spectrum caspase inhibitor IDN6734 was not protective in this model. To ascertain whether mitochondrial dysfunction downstream of these events was a required step, we utilized a peptide corresponding to residues 4-23 of Bcl-x(L) conjugated to the protein transduction domain of HIV TAT (TAT-BH4), which has been shown to protect mitochondria against Ca2+-induced deltaPsi(m) loss (2). TAT-BH4 attenuated CK release and loss of TTC staining, demonstrating the role of mitochondria and a pro-apoptotic Bcl-2 family member in the process leading to cell death. We propose the following pathway. (i) Reperfusion results in sodium influx followed by calcium accumulation. (ii) This leads to calpain activation, which in turn leads to Bid cleavage. (iii) Bid targets the mitochondria, causing dysfunction and release of pro-apoptotic factors, resulting in DNA fragmentation and death of the cell. Ischemia/reperfusion initiates a cell death pathway that is independent of caspases but requires calpain and mitochondrial dysfunction.
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PMID:Calpain and mitochondria in ischemia/reperfusion injury. 1204 24


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