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)

NGF and bFGF have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action are unknown. Since central neurons are particularly vulnerable to hypoglycemia that occurs with ischemia or insulin overdose, we tested the hypothesis that growth factors can protect neurons against hypoglycemic damage. NGF and bFGF each prevented glucose deprivation-induced neuronal damage in human cerebral cortical and rat hippocampal cell cultures (EGF was ineffective). Protection was afforded when the growth factors were administered before (NGF and bFGF) or up to 12 hr following (NGF) the onset of hypoglycemia. Direct measurements of intracellular calcium levels and manipulations of calcium influx demonstrated that sustained elevations in intracellular calcium levels mediated the hypoglycemic damage. NGF and bFGF each prevented the hypoglycemia-induced elevations of intracellular calcium. These findings indicate that growth factors can stabilize neuronal calcium homeostasis in central neurons and thereby protect them against environmental insults.
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PMID:NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis. 166 17

We have studied the development of the collateral circulation in the heart in response to gradual and progressive coronary artery occlusion. When the coronary stenosis becomes critical, tissue ischemia occurs, which we believe leads to the production (and probably to release from storage sites) of tissue hormones (mitogens) that lead to mitosis of endothelial and smooth muscle cells. We have identified from hearts several known mitogens (aFGF, bFGF), non-mitogenic angiogenic factors (TGF-beta), a new anti-mitogen, and a new myocyte-derived growth factor (structures of the last two not yet elucidated). An important principle in the development of collaterals is the remodeling of pre-existing small vessels into the much larger vascular structure. To accommodate new cells old structures have to be removed by controlled proteolysis (tPA, uPA, elastase).
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PMID:Angiogenesis in the adult heart. 171 53

Ischemia/hypoxia rapidly induce ischemic changes in vulnerable neurons: cortical neurons in layers II-III and V, hippocampal neurons, cerebellar Purkinje cells and certain basal ganglia and brainstem neurons. The ischemic changes are manifested histologically by nuclear pyknosis, cytoplasmic shrinkage and basophilia. These neurons exhibit strong and persistent expression of immediate early genes (IEGs): c-fos and c-jun. The onset of IEG expression is followed within a day by enhanced bFGF expression in non-ischemic neurons in the same general regions. The appearance of bFGF is followed within another day by proliferation of blood vessels, macrophages and glial cells around the infarct. The newly-formed blood vessels and macrophages migrate into the necrotic infarct aiming at disposal of the necrotic debris. The gliosis although concentrated around the infarct spreads to involve remote regions of both hemispheres. Based on the spatiotemporal correlation between cell proliferation and bFGF and the known mitogenic properties of bFGF, we believe that this molecule may be responsible for the late response in brain infarct including angiogenesis, gliosis and macrophage proliferation. The physiological roles of IEGs in the chain of adaptive response following brain infarction and its relationship with bFGF are subjects pending future investigations.
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PMID:Correlation between proto-oncogene, fibroblast growth factor and adaptive response in brain infarct. 756 83

To study the roles of bFGF and its receptor in the process of neuronal cell death and the wound repair response, we induced 10 min of transient global cerebral ischemia in rats and measured changes in expression of both bFGF and the FGF receptor, flg. CA1 pyramidal cells are selectively vulnerable to ischemia and die one to 3 days after 10 min of ischemia. In these cells, bFGF mRNA was induced by 6 hours, reached a maximal level by 24 h after ischemia, and subsequently decreased. Message for the FGF receptor, flg, was present in the pyramidal cells layer, and vanished almost completely in parallel with neuronal death. In the granule cell layer of dentate gyrus, the expression of bFGF mRNA increased more rapidly. It was maximal by 6 h and returned to the basal level by 3 days. In the hilus of the dentate gyrus, bFGF expression was maximal at 24 h and returned to control levels by 3 days. Despite the rapid changes in expression of bFGF mRNA, there was no significant change of bFGF immunoreactivity in either the CA1 pyramidal cell layer or in the granule cell layer of dentate gyrus within 3 days after ischemia. The apparent failure of the message to be efficiently translated supports the idea that translation is impaired under conditions where ischemia leads to delayed neuronal cell death. Expression of bFGF mRNA, FGFR mRNA and bFGF immunoreactivity increased dramatically in a broad area of CA1 subfield from 7 days until 30 days after ischemia because of increased expression by reactive glial cells. We suggest that these rapid and complex changes in the expression of bFGF mRNA and bFGF protein may be part of a coordinated response to ischemic injury that is designed to minimize the severity of neuron death.
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PMID:Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor. 801 96

Abnormal smooth muscle cell (SMC) proliferation is observed in several pathological situations such as atherosclerosis, pulmonary hypertension, and venous pathologies, resulting in a thickening of the vessel wall. If endothelial cells have been assumed to play a role in the triggering of this proliferation, no direct evidence is available. As ischemia is often linked to these situations, we exposed human umbilical vein endothelial cells (HUVEC) to hypoxia. The HUVEC-conditioned medium was then added to SMC and the proliferation of these cells was measured. We observed a pro-proliferative activity for SMC of the hypoxic HUVEC-conditioned medium but not of the normoxic HUVEC one. This pro-proliferative activity could not be inhibited if HUVEC were treated with cycloheximide but was blocked if the synthesis of prostaglandins by HUVEC was inhibited during hypoxia. PGD2, and especially PGF2 alpha at the concentration found in the hypoxic HUVEC-conditioned medium, were demonstrated to have a mitogenic effect on SMC. PGE2 also showed a pro-proliferative activity but at higher concentrations. In addition, the kinetics of increase in SMC proliferation induced by a mixture of the four prostaglandins at the corresponding concentrations was the same as the one observed with hypoxic HUVEC-conditioned medium. However, when tested on fibroblasts which do not respond to PGF2 alpha, hypoxic HUVEC-conditioned medium also had a pro-proliferative activity. In addition, anti-bFGF antibodies but not anti-PDGF blocked the mitogenic activity of this conditioned medium for SMC. Finally, the mitogenic effects of PGF2 alpha and of bFGF on SMC are additive. These results indicate that bFGF is probably also involved. These results indicate that these prostaglandins act in synergy with bFGF and are the molecules responsible for the pro-proliferative activity observed in hypoxic HUVEC-conditioned medium. We propose that these findings can explain the excessive growth of SMC in blood vessels following chronic ischemic situations.
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PMID:Hypoxia stimulates human endothelial cells to release smooth muscle cell mitogens: role of prostaglandins and bFGF. 802 Jun 5

Throughout evolution the brain has acquired elegant strategies to protect itself against a variety of environmental insults. Prominent among these are signals released from injured cells that are capable of initiating a cascade of events in neurons and glia designed to prevent further damage. Recent research has identified a remarkably large number of neuroprotection factors (NPFs), whose expression is increased in response to brain injury. Examples include the neurotrophins (NGF, NT-3, NT-5, and BDNF), bFGF, IGFs, TGFs, TNFs and secreted forms of the beta-amyloid precursor protein. Animal and cell culture studies have shown that NPFs can attenuate neuronal injury initiated by insults believed to be relevant to the pathophysiology of traumatic brain injury (TBI) including excitotoxins, ischemia, and free radicals. Studies of the mechanism of action of these NPFs indicate that they enhance cellular systems involved in maintenance of Ca2+ homeostasis and free radical metabolism. Recent work has identified several low-molecular-weight lipophilic compounds that appear to mimic the action of NPFs by activating signal transduction cascades involving tyrosine phosphorylation. Such compounds, alone or in combination with antioxidants and calcium-stabilizing agents, have proved beneficial in animal studies of ischemic brain injury and provide opportunities for development of preventative/therapeutic approaches for TBI.
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PMID:Endogenous neuroprotection factors and traumatic brain injury: mechanisms of action and implications for therapy. 820 25

Several cellular signaling systems have been implicated in the neuronal death that occurs both in development ("natural" cell death) or in pathological conditions such as stroke and Alzheimer's disease (AD). Here we consider the possibility that neuronal degeneration in an array of disorders including stroke and AD arises from one or more alterations in calcium-regulating systems that result in a loss of cellular calcium homeostasis. A long-standing hypothesis of neuronal injury, the excitatory amino acid (EAA) hypothesis, is revisited in light of new supportive data concerning the roles of EAAs in stroke and the neurofibrillary degeneration in AD. Two quite new concepts concerning mechanisms of neuronal injury and death are presented, namely: 1) growth factors normally "stabilize" intracellular free calcium levels ([Ca2+]i) and protect neurons against ischemic/excitotoxic injury, and 2) aberrant processing of beta-amyloid precursor protein (APP) can cause neurodegeneration by impairing a neuroprotective function of secreted forms of APP (APPs) which normally regulate [Ca2+]i. Altered APP processing also results in the accumulation of beta-amyloid peptide which contributes to neuronal damage by destabilizing calcium homeostasis; in AD beta-amyloid peptide may render neurons vulnerable to excitotoxic conditions that accrue with increasing age (e.g., altered glucose metabolism, ischemia). Growth factors may normally protect neurons against the potentially damaging effects of calcium influx resulting from energy deprivation and overexcitation. For example, bFGF, NGF and IGFs can protect neurons from several brain regions against excitotoxic/ischemic insults. Growth factors apparently stabilize [Ca2+]i by several means including: a reduction in calcium influx; enhanced calcium extrusion or buffering; and maintenance or improvement of mitochondrial function. For example, bFGF can suppress the expression of a N-methyl-D-aspartate (NMDA) receptor protein that mediates excitotoxic damage in hippocampal neurons. Growth factors may also prevent the loss of neuronal calcium homeostasis and the increased vulnerability to neuronal injury caused by beta-amyloid peptide. Since elevated [Ca2+]i can elicit cytoskeletal alterations similar to those seen in AD neurofibrillary tangles, we propose that neuronal damage in AD results from a loss of calcium homeostasis. The data indicate that a variety of alterations in [Ca2+]i regulation may contribute to the neuronal damage in stroke and AD, and suggest possible means of preventing neuronal damage in these disorders.
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PMID:Altered calcium signaling and neuronal injury: stroke and Alzheimer's disease as examples. 851 77

Angiogenic therapy using fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) is being developed as a novel therapeutic strategy to obtain restoration of blood flow around the ischemia in cases of ischemic cardiovascular disease. In addition, arterial gene therapy through gene transfer by VEGF genes has now reached the stage of clinical application. Through in vivo animal experiments to determine the angiogenic effects of FGF and VEGF, we hope to obtain clues concerning the clinical applications of these methods. Methods-1: Twenty-three adult dogs were divided into 3 groups as follows: Group A-1: 20 micrograms of bFGF was administered intravenously simultaneously with heparin three times per week in 4 dogs. Group A-2: 20 micrograms of bFGF was administered intravenously three times a week without heparin in 4 dogs. Group B: 20 micrograms of bFGF was administered intramuscularly three times per week in 5 dogs. Group C: Sham operation control group consisting of 10 dogs. Local ischemia was created in the hind limbs of animals in groups A-1, A-2 and B through ligation of the femoral artery. Selective femoral arteriography was performed immediately after ligation at 1 week and 2 weeks postoperatively. Biopsy was also performed either at 1 week or 2 weeks after ligation. Results-1: (1) The percent increase in number of collateral vessels of the ischemic zone, as recognized on arteriography, was greater in the bFGF groups compared to group C. (2) The increase in collateral vessels peaked at 1 week. (3) No difference in angiogenic effect was observed in relation to the method of administration. (4) The combined administration of heparin had no angiogenic effect. (5) The hemoglobin content of the biopsy specimens was significantly greater in the 3 groups receiving bFGF compared to group C. Methods-2: The same study was performed using VEGF as detailed in Method-1. Results-2: As in the first experiment, a significant increase in collateral vessels was seen in the VEGF group compared to the control group. Both exogenous bFGF and VEGF significantly promote collateral vessel development and appear to be effective novel therapeutic agents for the treatment of ischemic disease.
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PMID:Angiogenesis. Angiogenic therapy using fibroblast growth factors and vascular endothelial growth factors for ischemic vascular lesions. 877 22

The objective was to examine the changes in the capillary network in the left ventricle of rats subjected to transient occlusion of the left coronary artery followed by reperfusion (I-R). Eighteen Wistar rats were divided into three groups and all rats were anaesthetized with ethyl ether and artificially ventilated. The I-R 1 rats were subjected to a 3 min occlusion followed by reperfusion; the I-R 3 rats had three 3 min occlusions separated by 3 min of reperfusion; the Sham-operated rats underwent surgery but the coronary artery was not occluded. The thorax was closed at the end of the procedures and the rats were sacrificed for isolation of the hearts 30 d after treatment. Frozen sections of the left ventricles were cut and differential staining was used to classify the capillary portions. Five additional rats treated as the I-R 1 group were sacrificed at 120 min after reperfusion. Their left ventricles were used for immunohistochemical investigation of the early expression of bFGF and VEGF. By comparison with the Sham-operated rats, both I-R groups showed increases in the capillary density of total and venular capillary portions, an increased capillary : myocyte (C : M) ratio and a decrease in the capillary domain area in the three capillary portions. The changes in the I-R 1 group were significantly greater than those in the I-R 3 group, suggesting that the frequent experience of ischemic attack reduces the capacity of angiogenesis. In the rats sacrificed 120 min after the start of reperfusion, bFGF and VEGF were expressed on capillaries and in some myocytes. Punctate bFGF or VEGF staining was observed even 30 d after the transient ischemia. One 3 min occlusion of the left coronary artery followed by reperfusion produced changes in capillarity that would increase the oxygen supply to ventricular tissues. These effects may be attributed to the bFGF and VEGF expressed around capillaries. Repeated occlusions interspersed with a short period of reperfusion reduced the advantageous effects on capillarity.
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PMID:Effects of transient coronary occlusion on the capillary network in the left ventricle of rat. 953 78

Phosphate-activated glutaminase (PAG) activity decreases markedly in the early period of ischemia. The decrease of the enzyme activity is reversible if the ischemic period is relatively short, but it becomes irreversible after 90 minutes of ischemia. The deterioration is a functional damage of the retinas caused by ischemia. We studied effects of growth factors and neurotrophic factors on protection of PAG in the ischemic and reperfused rat retinas. Before ischemia, 1 microl of growth factors or neurotrophic factors (0.1 microg/microl for insulin-like growth factor-I [IGF-I], insulin-like growth factor-II [IGF-II], brain-derived neurotrophic factor [BDNF], nerve growth factor [NGF]; 1 microg/microl for basic fibroblast growth factor [bFGF]) were injected into the vitreous cavity of the left eyes of anesthetized Sprague Dawley rats. As a control, phosphate buffered saline was injected to the right eyes. To induce ischemia, we clamped left eyes for 90 minutes after bulbar conjunctival incision all around limbus. The rat retinas were homogenized with distilled water 1 day after reperfusion and used for PAG assay. Retinal ammonia concentration was also determined as a ischemic marker. About 80% decrease of retinal PAG activity and 50% increase of retinal ammonia concentration were observed after 90 minutes of ischemia and 1 day of reperfusion as compared with unoperated normal eyes. IGF-II, BDNF and NGF had protective effects on the retinal PAG activity, whereas IGF-I, bFGF, stable bFGF were less effective. In addition, IGF-II and BDNF suppressed elevation of retinal ammonia concentration. BDNF, NGF and IGF-II have marked effect on the protection of PAG activity in the ischemic and reperfused rat retinas, whereas bFGF, which is very effective for the protection of ischemic cell death, shows moderate effect.
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PMID:Administration of nerve growth factor, brain-derived neurotrophic factor and insulin-like growth factor-II protects phosphate-activated glutaminase in the ischemic and reperfused rat retinas. 1045 79


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