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)

Basic fibroblast growth factor (bFGF) is a biological active polypeptide with potent trophic effects on neurons, glia and endothelial cells. In the present study, we examined the temporal expression profile of bFGF protein in cultured cortical astrocytes under ischemic-like conditions such as serum-free, glucose-free or glutamate application. A peak increase of bFGF level was observed at 24 h after the initiation of insults. A striking increase in the bFGF immunoreactivity and a moderate increase in the fibroblast growth factor receptor-1 (FGFR-1) immunoreactivity were also found in the astrocytes treated with serum- or glucose-deprivation or glutamate. The increased bFGF immunoreactivity and FGFR-1 immunoreactivity were mainly accumulated in the nuclei of astrocytes. The results suggest that the expression of bFGF and FGFR-1 in the astrocytes, especially in the nuclear interior, can be up-regulated under ischemic-like conditions and that the up-regulation of bFGF and FGFR-1 may play an important role in the maintenance and repair of the central nervous system (CNS) after ischemia.
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PMID:Increased expression and nuclear accumulation of basic fibroblast growth factor in primary cultured astrocytes following ischemic-like insults. 1052 71

Basic fibroblast growth factor (FGF-2) may protect the heart from ischemia-reperfusion injury (stunning) by stimulating nitric oxide (NO) production. To test this hypothesis, we pretreated coronary-perfused mouse hearts with 1 microg/ml FGF-2 or vehicle control before the onset of ischemia. Intracellular calcium (Ca(i)(2+)) was estimated by aequorin, and NO release was measured with an NO-selective electrode. Hearts perfused with FGF-2 maintained significantly better left ventricular (LV) function during ischemia than hearts perfused with vehicle. FGF-2 significantly delayed the onset of ischemic contracture and improved LV recovery during reperfusion. Ca(i)(2+) was similar in both groups at baseline during ischemia and reperfusion. L-N(6)-(1-iminoethyl)lysine, a selective inhibitor of inducible NO synthase (NOS2), obliterated the protective effects of FGF-2. In transgenic hearts deficient in the expression of NOS2 (NOS2-/-), FGF-2 did not attenuate ischemia-induced LV dysfunction. Measurements of NO release demonstrated that FGF-2 perfusion significantly increased NO in wild-type but not in NOS2-/- hearts. We conclude that basic FGF attenuates myocardial stunning independent of alterations in Ca(i)(2+) by stimulating NO production via an NOS2-dependent pathway.
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PMID:Basic FGF reduces stunning via a NOS2-dependent pathway in coronary-perfused mouse hearts. 1089 65

Basic fibroblast growth factor (bFGF) is a polypeptide with potent survival-promoting and protective effects on brain cells. In previous studies, we showed that intravenous administration of bFGF reduced infarct volume in models of focal cerebral ischemia in rats, mice, and cats. In these previous studies, infarct volume was measured within 1-7days of the onset of ischemia. The current study was undertaken to determine whether the reduction in infarct volume by bFGF was persistent beyond the first week after stroke. Mature male Sprague-Dawley rats received an intravenous infusion of bFGF (50 microg/kg per h) or vehicle during 0.5-3.5h after permanent proximal middle cerebral artery occlusion. We found a 27% reduction in infarct volume in bFGF- compared to vehicle-treated animals at three months after infarction (P<0.05). The data show that intravenous bFGF treatment produces a persistent reduction in infarct volume, at least up to three months following focal stroke.
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PMID:Intravenous basic fibroblast growth factor produces a persistent reduction in infarct volume following permanent focal ischemia in rats. 1117 28

The article discusses the role of vascular endothelial growth factor(VEGF) in angiogenesis in embryonic development, particularly the effect of VEGF on capillary formation in response to chronic tissue ischemia and hypoxia. The sources and action of numerous angiogenic and angiostatic factors responsible for morphologic development of endothelial cells and disturbances in VEGF and FGF secretion are also presented. Increased VEGF and VEGF receptor expression enhances vascular permeability and angiogenesis, and is the cause of tissue edema as well as tumor and metastasis formation. VEGF appears to have a beneficial effect only in ischemic diseases of the heart and peripheral vessels. The article highlights the therapeutic implication of VEGF suppression in other areas of ischemia.
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PMID:Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. 1120 53

Basic fibroblast growth factor (FGF-2) is a pleiotropic mitogen which plays an important role in cell growth, differentiation, migration, and survival in different cells and organ systems. Recently, several clinical applications for FGF-2 gene transfer are being evaluated in wound healing and collateral artery development to relieve myocardial and peripheral ischemia due to the ability of FGF-2 to regulate the growth and function of vascular cells. However, FGF-2 lacks a classical hydrophobic secretion signal peptide, the FGF-2 chimeras containing various signal sequences have been explored. In this study, a novel recombinant 4sFGF-2 was constructed by replacing nine residues from the amino-terminus of native FGF-2 (Met1 to Leu9) with eight amino acid residues of signal peptide of FGF-4 (Met1 to Ala8) to better increase the secretion level of FGF-2. When the recombinant FGF-2 gene, cloned into the expression vector with CMV promoter, was expressed in COS-7 cells, the recombinant 4sFGF-2 was highly secreted into the media. The secreted 4sFGF-2 showed the same biological activity as the native FGF-2 in the dose-response effects on DNA synthesis and cell growth of rat aortic smooth muscle cells (RASMCs) and NIH3T3 cells. The 4sFGF-2 also was able to activate MAPK as wild FGF-2 in RASMCs. These results indicate that a novel recombinant 4sFGF-2 may be useful as clinical applicability of angiogenic growth factor gene transfer.
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PMID:A novel recombinant basic fibroblast growth factor and its secretion. 1140 82

After trauma injury to the musculoskeletal system, conditions such as ischemia and inflammation involve excess production of superoxide (O2*), nitric oxide (*NO), and their reaction product, peroxynitrite (ONOO-). Exposure of murine osteoblasts and rat-derived primary osteoblast precursors to ONOO- resulted in a dose- and time-dependent delayed cell death that was more characteristic of apoptosis than necrosis. Exposure of both cell populations to ONOO- immediately enhanced phosphorylation and nitration of tyrosine residues within several polypeptides. Treatment of osteoblasts and osteoblast precursors with exogenous acidic fibroblast growth factor (FGF-1) enhanced cellular growth, increased endogenous levels of tyrosine phosphorylation, and significantly induced expression of both osteopontin and osteocalcin messenger RNA (mRNA) as well as osteopontin protein. Pretreatment of both cell populations with exogenous FGF-1 prevented ONOO(-)-mediated death. Cell signaling induced by FGF-1 pretreatment had no major effect of total levels of tyrosine nitration after ONOO- treatment. Collectively, these in vitro efforts show that FGF-1 signaling renders osteoblasts and osteoblast precursors resistant to the cytotoxic effects of ONOO-. Consequently, results presented here predict the therapeutic use of this growth factor for promoting the progression of bone repair mechanisms after fracture trauma.
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PMID:Acidic fibroblast growth factor signaling inhibits peroxynitrite-induced death of osteoblasts and osteoblast precursors. 1158 58

Basic fibroblast growth factor (bFGF) is an important angiogenic factor produced by hearts subjected to ischemia. However, the direct effects of bFGF on myocardial cells are unknown. Primary cultured cardiac myocytes from neonatal rats were stimulated with lipopolysaccharide (LPS), a potent inducer of inducible nitric oxide synthase (iNOS), in the presence or the absence of bFGF. LPS induced the expression of iNOS in cardiac myocytes, demonstrated at both mRNA and protein levels. We showed that LPS activated the apoptotic pathway, evidenced by TUNEL staining, DNA ladder formation, and morphologic features. LPS-induced apoptosis was blocked by the administration of L-NAME, an inhibitor of NOS. This indicates that LPS induces apoptosis via an iNOS-dependent pathway. Administration of bFGF completely inhibited myocardial cell apoptosis induced by hydrogen peroxide or acidic medium as well as LPS. To determine signaling pathways for this inhibitory effect, we utilized PD098059, an MEK-1-specific inhibitor. PD098059 blocked bFGF-induced activation of ERK (extracellularly responsive kinase)-1/2 and neutralized the apoptotic inhibitory effect of bFGF. These findings demonstrate that LPS induces myocardial cell apoptosis in an iNOS-dependent manner. The results also suggest that bFGF is a protective factor against myocardial cell apoptosis and that this protection requires the MEK-1-ERK pathway.
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PMID:Basic fibroblast growth factor protects cardiac myocytes from iNOS-mediated apoptosis. 1180 11

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 microg/kg for 6 sequential weeks (total dose 12 microg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.
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PMID:Proteinuria in a placebo-controlled study of basic fibroblast growth factor for intermittent claudication. 1195 89

Basic fibroblast growth factor (bFGF) has minimal pharmacological effects in the central nervous system in the absence of blood-brain barrier (BBB) disruption. BBB transport of bFGF occurs via an absorptive-mediated transcytosis mechanism, which is relatively inefficient. To enhance the BBB transport of bFGF, this neurotrophin was reformulated to enable receptor-mediated transport across the BBB via the transferrin receptor. bFGF was monobiotinylated and coupled to a BBB drug-delivery vector comprised of streptavidin (SA) and the OX26 monoclonal antibody to the rat transferrin receptor. The entire conjugate of biotinylated bFGF bound to the OX26-SA is designated bio-bFGF/OX26-SA. The bFGF retains receptor-binding affinity and has increased brain uptake following conjugation to OX26-SA. The bio-bFGF/OX26-SA conjugate protects cortical cell cultures against hypoxia/reoxygenation insult in a dose-dependent manner in vitro. A single intravenous injection of bio-bFGF/OX26-SA, equivalent to a dose of 25 microg/kg bFGF, produces an 80% reduction in infarct volume in the brain of rats subjected to permanent occlusion of the middle cerebral artery in parallel with a significant improvement of neurologic deficit. The neuroprotection is time-dependent, and there is a 67% reduction in stroke volume if the conjugate is administered at 60 min after arterial occlusion, whereas no significant reduction in stroke volume is observed if treatment is delayed 2 h. In conclusion, neuroprotection in regional brain ischemia is possible following the delayed intravenous injection of low doses of bFGF providing the neurotrophin is conjugated to a BBB drug-targeting system.
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PMID:Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. 1196 Oct 63

The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases that determines the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or skeletal muscle may be sufficient to preserve tissue integrity and/or function, and may thus be considered to be therapeutic. Innovative gene technologies and advances in animal modeling have enabled research scientists to develop therapeutic angiogenesis strategies applied in animal models of limb or myocardial ischemia and in treatment of patients with peripheral vascular obstruction or coronary artery diseases. Several therapeutic strategies have been proposed and tested even at the clinical level. Recent studies have established the feasibility of using recombinant angiogenic growth factors (mainly VEGF and FGF) to enhance angiogenesis in patients with limb or myocardial ischemia. Angiogenesis therapies using cells as a support for growth factor delivery or using endothelial progenitor cells which may directly participate in the angiogenic process have also been developed. Finally, one potential alternative strategy may be the use of drugs with pro-angiogenic activity, available in an oral formulation and which are currently administered to patients for treatment of different pathologies. All strategies of angiogenesis therapy currently being tested have the potential to be effective in the treatment of ischemic disease. However, such strategies may cause harmful side effects which emphasize the need to be aware of the biological effects of each angiogenic agent proposed for clinical studies.
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PMID:Angiogenesis therapy in ischemic disease. 1199 34


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