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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factors (FGF) and type beta-1 transforming growth factor (TGF beta 1) are pleiotropic regulatory peptides which are expressed in myocardium in a precise developmental and spatial program and are up-regulated, in the adult heart, by ischemia or a hemodynamic burden. The accumulation of trophic factors after aortic banding supports the hypothesis that autocrine or paracrine pathways might function to mediate, in part, the consequences of mechanical load. Our laboratory has demonstrated that cardiac muscle cells are targets for the action of peptide growth factors and, more specifically, that modulation of the cardiac phenotype by basic FGF (bFGF) and TGF beta 1 strongly resembles the induction of fetal cardiac genes--including skeletal alpha-actin (SkA), beta-myosin heavy chain, and atrial natriuretic factor--which are characteristic of pressure-overload hypertrophy. Unexpectedly, and despite effects like those of bFGF on five other cardiac genes, acidic FGF (aFGF) was found to repress, rather than stimulate, SkA transcription in neonatal cardiac muscle cells. The proximal 200 nucleotides of a heterologous SkA promoter were sufficient for basal tissue-specific transcription, for induction by bFGF, and for inhibition by aFGF. Thus, both positive and negative regulation by peptide growth factors can be localized to the proximal SkA promoter. Full promoter activity required each of three CC[A/T]6GG motifs similar to the serum response element (SRE) for activation of the c-fos proto-oncogene, as previously shown for SkA transcription in a skeletal muscle background. The most proximal SRE, SRE1, was sufficient in the absence of other SkA promoter sequences for efficient tissue-specific expression in cardiac myocytes (versus cardiac fibroblasts), and was stimulated by bFGF to the same extent as the full-length promoter and endogenous gene. Despite its ability to repress the SkA promoter, aFGF had no significant effect on SRE1. Both FGFs up-regulated the canonical fos SRE, to a comparable degree. Thus, SRE1 can discriminate between signals generated in cardiac myocytes by bFGF and aFGF. In cardiac myocyte extracts, two predominant proteins contact SRE1: serum response factor (SRF) and a second protein, F-ACT-1. Thus, serum response factor and F-ACT-1 are candidate trans-acting factors for basal transcription of the SkA gene in cardiac muscle cells and for induction of SkA by bFGF and, potentially, other trophic signals.
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PMID:Growth factors, growth factor response elements, and the cardiac phenotype. 128 69

Astrocytic activation plays a major role in homeostatic maintenance of the central nervous system in response to neuronal damage. To assess the reactivity of astrocytes in transient cerebral ischemia of the gerbil, we studied the levels of glial fibrillary acidic protein (GFAP) and its mRNA. GFAP mRNA increased by 4 h after carotid artery occlusion, reached peak levels by 72 h with a 12-fold increase over control and then started declining as early as 96 h postischemia. An examination of the specific regions of the brain revealed an increase in GFAP mRNA associated with the forebrain, midbrain, hippocampus and striatum. GFAP mRNA in the non-ischemic cerebellum however, remained expressed at constitutively low levels. Immunoblot analysis with anti-GFAP antibodies demonstrated a 2- to 3-fold increase in the protein after 24 and 48 h of reperfusion. Pretreatment with pentobarbital and 1-(5'-oxohexyl)-3-methyl-7-propyl xanthine (HWA 285), the drugs that have been shown to protect against ischemic damage, prevented the increase in GFAP mRNA in the cortex following ischemic injury. Forebrain ischemia also induced vimentin mRNA and protein quantities by 12 h of reperfusion in the cortex. The levels of c-fos and preproenkephalin mRNA increased rapidly within 1 h after ischemic injury, demonstrating a temporal difference in mRNA changes following ischemia. These results indicate that an increase in GFAP and vimentin, the two glial intermediate filament proteins in the area of the ischemic lesion may be associated with a glial response to injury.
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PMID:Transient ischemia stimulates glial fibrillary acid protein and vimentin gene expression in the gerbil neocortex, striatum and hippocampus. 131 93

To understand the complex mechanism(s) involved in molecular responses to ischemia, we developed two experimental models in pigs. In a "stunning" model of repetitive ischemia and reperfusion, we studied the mRNA expression of immediate early genes like c-fos, c-myc and heat shock protein-70 (HSP-70). Myocardial stunning was achieved by two cycles of 10-min left anterior descending coronary artery (LAD) occlusion and 30 min reperfusion. We observed several-fold enhanced expression of c-fos and HSP-70 mRNA in the stunned myocardium as compared with the control, whereas c-myc mRNA levels remained almost unchanged. In the second model, we examined the expression of the peptide mitogens heparin-binding growth factor 1 (HBGF-1) and transforming growth factor beta 1 (TGF-beta 1) after a chronic coronary artery occlusion leading to myocardial collateralization. Progredient stenosis of the circumflex coronary artery was induced by implanting a hygroscopic ameroid constrictor ring around it and occlusion was verified by in vivo angiography. Using polymerase chain reaction (PCR) and Northern hybridization techniques, we observed significantly enhanced expression of HBGF-1 and TGF-beta 1 in collateralized myocardium as compared with normal. In situ techniques revealed the localization of HBGF-1 transcripts in the blood vessel wall, and TGF-beta 1 in cardiac myocytes and Purkinje cells. Our results clearly indicate that myocardial stunning stimulates the expression of transcription factors which might be involved in regulation of certain growth factors like HBGF-1 and TGF-beta 1 which may play a significant role in the development of a collateral circulation.
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PMID:Molecular biology of the coronary vascular and myocardial responses to ischemia. 138 Jun 15

The molecular basis of myocardial adaptation to ischemia and reperfusion is poorly understood. It is thought that nuclear proto-oncogenes act as third messengers, converting cytoplasmic signal transduction into long-term changes of gene expression. We studied the expression of six nuclear proto-oncogenes (Egr-1, c-fos, fosB, c-jun, junB, and c-myc) in myocardium subjected to ischemia and reperfusion in anesthetized pigs. Stunning was achieved by two 10-minute left anterior descending coronary artery occlusions separated by 30 minutes of reperfusion. Hearts were excised after the first occlusion, after the first reperfusion, and at 30, 120, 150, and 210 minutes of reperfusion after the second occlusion. Total RNA was prepared from stunned as well as normally perfused myocardial tissue and subjected to Northern blotting. The response of the six nuclear proto-oncogenes varied.fosB gene expression was never detected. The c-myc gene was expressed, but its level was unchanged by ischemia. c-jun expression was slightly increased by ischemia (3.1 +/- 0.6-fold). The c-fos, Egr-1, and junB genes were highly induced, being fivefold to sevenfold higher in experimental than in control tissue. In three animals pretreated with the beta 1-antagonist metoprolol and then subjected to the above experimental protocol, the induction of proto-oncogenes was similar to that in nonblocked controls. Our results show that the myocardial adaptive response to ischemic stress includes the induction of at least four transcription factors that may be further operative in repair processes and angiogenesis.
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PMID:Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion. 138 5

Hydrogen peroxide (H2O2) is a type of active oxygen species produced mainly in blood by inflammation, ischemia or anoxia. Treatment of rat neonatal cortical astrocytes in culture with 0.2-1.0 mM H2O2 which is lethal for hippocampal neurons, increases nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) mRNA content in a time dependent manner. H2O2 also increases c-fos mRNA expression, which is probably involved in the gene regulation of both NGF and bFGF. Maximal induction was reached after 6 h of incubation (5.7-fold increase in NGF and 2.4-fold induction of bFGF mRNA). Hydrogen peroxide induced bFGF and NGF gene expression suggests that neurotrophic factors in astrocytes could be induced by lesion, consistent with their protective function in the CNS.
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PMID:Free radicals induce gene expression of NGF and bFGF in rat astrocyte culture. 139 49

Cerebral ischemia induces the expression of a number of proteins that may have an important influence on cellular injury. The purpose of this study was to compare the regional effects of hypoxia-ischemia on the expression of the proto-oncogene, c-fos, and the heat shock protein-70 (HSP-70) gene in developing brain. Unilateral hypoxia-ischemia was produced in the brain of immature rats (7, 15, and 23 days after birth) using a combination of carotid artery ligation and systemic hypoxia (8% O2). After recovery for 2 and 24 h, the regional expression of c-fos and HSP-70 mRNA was determined using in situ hybridization. Littermates were permitted to recover for 1 week for assessment of histologic injury. Hypoxia-ischemia increased the expression of both c-fos and HSP-70 mRNA, but the topography of expression varied with the age of the animal as well as the mRNA species. In the 7-day-old group, expression of c-fos at 2 h increased in multiple regions of the ipsilateral hemisphere in nearly one-half of the animals, while HSP-70 mRNA was not expressed until 24 h and, then, predominantly in the hippocampus. In 15- and 23-day-old rats, expression of c-fos was increased at 2 h in the entorhinal cortex and in the dendritic field of the upper blade of the hippocampal dentate gyrus, while HSP-70 mRNA was prominently expressed in neocortex and the cell layers of the hippocampus. Interestingly, the strong expression of HSP-70 mRNA in dentate granule cells did not occur in the innermost layer of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regional expression of c-fos and heat shock protein-70 mRNA following hypoxia-ischemia in immature rat brain. 140 Jun 53

Blood reperfusion after temporary liver ischemia induces the expression of heat shock genes and the synthesis of heat shock proteins (hsps), in particular hsp 70. Induction requires a certain duration of ischemia, suggesting that cell damage before reperfusion is essential for activation of heat shock genes. The expression of the hsp 70 gene is preceded by activation of the cellular protooncogenes c-fos and c-jun. However, the product of these genes, which is transcription factor AP-1, seems unnecessary for activation of the hsp 70 gene, which does not require the integrity of protein synthesis. Hsp genes seem to behave as "early response genes," enabling the cell to respond to emergency situations.
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PMID:Stress proteins and reperfusion stress in the liver. 148 45

In situ hybridization was used to estimate regional levels of heat shock protein-70 (HSP-70) mRNA and c-fos mRNA in two related models of focal cerebral ischemia. In the first model, permanent occlusion of the distal middle cerebral artery (MCA) alone caused a patchy increase in HSP-70 mRNA by 1 h in the central zone of the MCA territory of the ipsilateral neocortex. Tissue levels of HSP-70 mRNA continued to increase for several hours and remained elevated at 24 h. In contrast to the focal expression of HSP-70, c-fos mRNA was increased throughout the ipsilateral cerebral cortex by 15 min and remained elevated for least 3 h. The wide distribution of c-fos expression suggests it may have been caused by spreading depression. In the second model, severe focal ischemia was produced with a combination of transient (1-h) bilateral carotid artery occlusion and permanent MCA occlusion. Combined occlusion for 1 h without reperfusion caused expression of HSP-70 mRNA only in regions adjacent to the central zone of the MCA territory of the neocortex. However, reperfusion of the carotids for 2 h generated intense expression of HSP-70 mRNA throughout most of the ipsilateral cerebral cortex, white matter, striatum, and hippocampus. The wide-spread increase in HSP-70 mRNA suggests that reperfusion triggered expression in all previously ischemic regions. However, at 24 h of reperfusion, increased levels of HSP-70 mRNA were restricted primarily to the ischemic core of the neocortex. These results suggest that expression of HSP-70 mRNA is prolonged in regions undergoing injury, but is transient in surrounding regions that recover.
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PMID:Regional expression of heat shock protein-70 mRNA and c-fos mRNA following focal ischemia in rat brain. 154 93

Kynurenic acid is the only known endogenous excitatory amino acid receptor antagonist in the central nervous system. In the present study, we examined whether increasing brain concentrations of kynurenic acid by loading with its precursor L-kynurenine, or blocking its excretion with probenecid, could exert neuroprotective effects. Neuroprotective effects were examined in a neonatal model of hypoxia-ischemia, and following intrastriatal injection of N-methyl-D-aspartate (NMDA). Seven-day-old rats underwent unilateral ligation of the carotid artery, followed by exposure to 8% oxygen for 1.5 h. L-kynurenine administered 1 h before the hypoxia-ischemia showed a dose-dependent significant neuroprotective effect, with complete protection at a dose of 300 mg kg-1. The induction of c-fos immunoreactivity in cerebral cortex was also blocked by this dose of L-kynurenine. Probenecid alone had moderate neuroprotective effects, while a combination of a low dose of probenecid with doses of 50-200 mg kg-1 of L-kynurenine showed significant dose-dependent neuroprotection. Kynurenine dose-dependently protected against NMDA neurotoxicity in 7-day-old rats. Neurochemical analysis confirmed that L-kynurenine with or without probenecid markedly increased concentrations of kynurenic acid in cerebral cortex of 7-day-old rats. These results show for the first time that pharmacologic manipulation of endogenous concentrations of kynurenic acid can exert neuroprotective effects.
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PMID:Neuroprotective effects of L-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats. 156 35

The expression profile of neurotrophin-3 (NT-3) mRNA in the rat hippocampus after forebrain ischemia was investigated by Northern blot and S1 nuclease protection analyses. The NT-3 transcripts in the hippocampus immediately decreased after ischemic insult, became undetectable within 3 h and remained at undetectable levels for at least 7 days. In contrast, the expression of c-fos and c-jun mRNA transiently increased both in the cerebral cortex and in the hippocampus. These results suggest that brain ischemia triggers dynamic changes in gene expression including a neurotrophic factor, which may cause functional and/or morphological changes of the neuronal network.
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PMID:Decreased expression of neurotrophin-3 mRNA in the rat hippocampus following transient forebrain ischemia. 161 77


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