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)

Locally produced cytokines and growth factors may mediate tissue remodelling processes, as observed in renal transplants exposed to ischemia or acute rejection episodes. The present study was designed to investigate mRNA transcript levels of platelet-derived growth factor (PDGF)-receptor beta, PDGF-A, PDGF-B, fibroblast growth factor-1, and transforming growth factor beta 1 in normal rat kidneys, in kidneys following contralateral nephrectomy and in renal transplants with acute or chronic rejection. Platelet-derived growth factor-receptor beta mRNA levels increased significantly in syngeneic and allogeneic transplants in the first week after transplantation and in allogeneic transplants with chronic rejection. Immunohistochemistry showed induction of PDGF-receptor beta protein expression on vascular wall cells in such grafts. Platelet-derived growth factor-A chain mRNA levels increased in day 3 allografts and in syngeneic LEW grafts, while PDGF-B chain mRNA levels showed no significant changes with transplantation. Fibroblast growth factor-1 mRNA levels were detectable in normal kidneys, tended to decrease with acute rejection, and increased significantly in chronic rejection. Transforming growth factor-beta 1 transcripts increased in acute and chronic rejection; immunohistochemistry showed predominantly glomerular localization of the transforming growth factor-beta 1 protein. We conclude that transplantation and rejection are associated with changes in the intragraft mRNA levels for several growth factors; chronic rejection is characterized by an increase in fibroblast growth factor-1 and transforming growth factor-beta 1 transcript levels.
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PMID:Growth factor transcripts in rat renal transplants. 880 45

Fibroblast growth factors (FGFs) are a family of nearly twenty heparin-binding growth factors. They are widely distributed throughout the body, but their activity is tightly controlled. This review will focus on fibroblast growth factor-1/FGF-1) and fibroblast growth factor-2 (FGF-2) which have been studied extensively in vitro and in vivo. These two growth factors stimulate the proliferation of cells of mesenchymal origin, including the three principal vascular cell types: fibroblasts, endothelial cells and smooth muscle cells. The molecular characteristics of these growth factors, their receptors, distribution, function, pharmacokinetics, hemodynamic effects and toxicity are reviewed herein. The experimental evidence for the potential for FGFs as therapeutic agents for the treatment of progressive myocardial ischemia, acute myocardial ischemia, and peripheral limb ischemia is also analyzed. It is not known to what extent the results of animal studies can be extrapolated to humans with ischemic cardiovascular disease. Clinical trials have been initiated, and there is a growing hope that the pharmacologic use of growth factors will represent a viable therapeutic alternative for patients with ischemic cardiovascular disease.
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PMID:Fibroblast growth factor-mediated angiogenesis for the treatment of ischemia. Lessons learned from experimental models and early human experience. 983 78

Fibroblast growth factor-2 (FGF-2), administered to the isolated rat heart by perfusion and under constant pressure, is protective against ischemia-reperfusion (I-R). Here we have investigated whether FGF-2 cardioprotection: (a) is dependent on flow modulation; (b) is linked to effects on contractility; (c) is mediated by protein kinase C (PKC); and (d) is linked to PKC and/or mitogen activated protein kinase (MAPK) associated with the sarcolemma. The isolated rat heart was used as a model. Under conditions of constant flow FGF-2 induced significant improvement in recovery of contractile function during I-R. Under constant perfusion pressure, FGF-2 induced a negative inotropic effect (15% decrease in developed pressure). Chelerythrine, a specific PKC inhibitor, prevented both the FGF-2-induced negative inotropic effect before ischemia, and cardioprotection during I-R. FGF-2 induced a chelerythrine-preventable, five-fold increase in sarcolemmal calcium-independent PKC activity. It also increased the association of PKC subtypes -epsilon and -delta with sarcolemmal membranes, detected by Western blotting, as well as, for PKC delta, by immunolocalization. FGF-2 increased the association of PKC epsilon with the membrane fraction of adult cardiomyocyte in culture, confirming that it can affect PKC signaling in cardiomyocytes directly and in a manner similar to its effects in situ. Finally, FGF-2 induced increased active MAPK at sarcolemmal as well as cytosolic sites. Active sarcolemmal MAPK remained elevated when the FGF-2-induced protection was prevented by chelerythrine. In conclusion, we have provided evidence that cardioprotection by FGF-2 is independent of flow modulation. PKC activation mediates both the FGF-2-induced negative inotropic effect before ischemia and the cardioprotective effect assessed during reperfusion, suggesting a cause and effect relationship. Furthermore, FGF-2 cardioprotection is linked to targeting of sarcolemmal sites by calcium-independent PKC.
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PMID:FGF-2-induced negative inotropism and cardioprotection are inhibited by chelerythrine: involvement of sarcolemmal calcium-independent protein kinase C. 999 May 40

Fibroblast growth factor (FGF)-1 plays important roles during myocardial and coronary morphogenesis. FGF-1 is also involved in the physiological response of the adult heart against ischemia, which includes cardiomyocyte protection and vascular growth. In the present study, we have generated transgenic mice with specific myocardial overexpression of the gene. Transgene expression was verified by Northern blot, and increased FGF-1 protein content was assessed by Western blot and immunoconfocal microscopy. Anatomic, histomorphological, and ultrastructural analyses revealed no major morphological or developmental abnormalities of transgenic hearts. Capillary density was unaltered, whereas the density of coronary arteries, especially arterioles, was significantly increased, as was the number of branches of the main coronary arteries. In addition, the coronary flow was significantly enhanced in transgenic mice ex vivo. These differences in the anatomic pattern of the coronary vasculature are established during the second month of postnatal life. The present findings demonstrate an important role of FGF-1 in the differentiation and growth of the coronary system and suggest that it is a key regulatory molecule of the differentiation of the arterial system.
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PMID:Transgenic myocardial overexpression of fibroblast growth factor-1 increases coronary artery density and branching. 1092 65

Fibroblast growth factors (FGFs) are polypeptides with various biological activities in vivo and in vitro, and their receptors are expressed in the widespread and specific neuronal populations of the brain. In this study, we asked whether keratinocyte growth factor (KGF), one of the FGF superfamily, would express in the brain, and have neuroprotective against ischemic brain injury. In situ hybridization analysis revealed that intense silver grains for KGF mRNA are observed in the neuronal cells of the cerebral cortex, hippocampus and amygdala in gerbil brain. Continuous cerebroventricular infusion of KGF (20 microg) for a 7 day period to gerbils starting 2 days before temporary right carotid artery occlusion (20 min) resulted in a higher survival rate than seen in vehicle-treated ischemic animals. Subsequent histological examinations showed that KGF effectively prevented delayed neuronal death of the hippocampal CA1 region. In situ detection of DNA fragmentation (TUNEL staining) revealed that ischemic animals infused with KGF contained fewer TUNEL-positive neurons in the hippocampal CA1 field than those infused with vehicle alone at the forth and seventh day after ischemia. KGF-treated brain showed over-expression of KGF mRNA in the neuronal cells of the cerebral cortex, hippocampus only in the right hemisphere, which was the side of carotid artery occlusion, 8-10 h after ischemia. These findings suggest that KGF has a protective effect against ischemic hippocampal neuronal damage in vivo, which may provide a new therapeutic strategy in the survival and reconstruction of neurons in response to cerebral injury.
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PMID:Keratinocyte growth factor prevents ischemia-induced delayed neuronal death in the hippocampal CA1 field of the gerbil brain. 1120 Oct 95

Fibroblast growth factor-2 (FGF-2) is a heparin-binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 (rFGF-2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF-2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF-2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 micrograms/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexes. Infusion of rFGF-2 was associated with changes in acute hemodynamics. While a clear PK/PD dose-response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF-2 doses was observed.
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PMID:Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease. 1130 94

Fibroblast growth factor 2 (FGF-2) immunoreactivity (IR) was examined in the ependyma and choroid plexus (CP) of lateral and third ventricles in normal adult rats, as well as in response to transient forebrain ischemia (TFI) and exogenous FGF-2 delivered intraventricularly for several days by osmotic pump. Similar patterns of FGF-2 IR were seen in the CP epithelia of both lateral and third ventricles, as well as in ependymal cells of the third ventricle and along lateral sides of the lateral ventricles. Consistent staining was seen along the apical aspect of epithelial cells facing the cerebrospinal fluid (CSF). Cytoplasmic staining was seen in the absence of ischemia, and was dramatically reduced in response to TFI. FGF-2 treatment followed by TFI resulted in sustained FGF-2 IR within CP and ependymal cells, supporting the idea that these tissues are involved in synthesis and secretion of growth factors into the CSF. In contrast, along the medial sides of the lateral ventricles, adjacent to brain structures such as the hippocampus, consistent staining was seen along the basal aspect of the ependymal cells. We propose that at least some regions of ependyma may function to transport molecules such as FGF-2 directly into the underlying brain parenchyma.
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PMID:FGF-2 immunoreactivity in adult rat ependyma and choroid plexus: responses to global forebrain ischemia and intraventricular FGF-2. 1142 15

Fibroblast growth factor-2 (FGF-2) is cardioprotective when added exogenously, stimulates cardiac myocyte proliferation, and is a mediator of tissue repair after injury. Furthermore, transgenic (TG) mice overexpressing FGF-2 in cardiac muscle demonstrate increased resistance to injury in an isolated heart model of ischemia-reperfusion. We investigated how increasing the endogenous FGF-2 levels in the heart affects the extent of myocardial damage induced by isoproterenol in vivo. Histopathological evaluation of hearts after intraperitoneal injection of isoproterenol yielded significantly higher scores for myocardial damage in FGF-2 TG lines compared with non-TG mice. After 1 day, FGF-2 TG mouse hearts displayed more cellular infiltration correlating with increased tissue damage. Immunostaining of non-TG and FGF-2 TG mouse hearts showed the presence of leukocytes in the infiltrate, including T cells expressing FGF receptor-1. Treatment of mice with T cell suppressors cyclosporin A and anti-CD3epsilon significantly decreased the level of myocardial injury observed after isoproterenol and equalized the histopathology scores in FGF-2 TG and non-TG hearts. These data demonstrate a direct T cell involvement in the response to isoproterenol-induced injury in vivo. Moreover, the findings indicate that the exacerbation of myocardial damage in FGF-2 TG mice was dependent on T cell infiltration, implicating FGF-2 in the inflammatory response seen in cardiac tissue after injury in vivo.
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PMID:Exacerbation of myocardial injury in transgenic mice overexpressing FGF-2 is T cell dependent. 1178 2

Fibroblast growth factor-2 (FGF-2) is a potent regulator of many cellular functions and phenomena, including cell proliferation, differentiation, survival, adhesion, migration, motility and apoptosis, and processes such as limb formation, wound healing, tumorigenesis, angiogenesis, vasculogenesis and blood vessel remodeling. In the adult myocardium, FGF-2 is expressed by various cell types, including cardiomyocytes, fibroblasts and smooth muscle cells. The biological effects of FGF-2 in the myocardium are mediated by the high-affinity tyrosine kinase receptor FGFR-1, the major FGF receptor in the heart. Here, we give an overview of current insights into the multiple roles of FGF-2 in the myocardium, as they pertain to two basic phenomena: ischemia-reperfusion injury and cardiac hypertrophy. The first category includes roles for FGF-2 in cardioprotection, the inflammatory response, angiogenesis and vascular remodeling, while the second includes myocyte hypertrophy, fibrosis, and gap junction functioning (conduction). Given the strong evidence for FGF-2 as both a cardioprotective and angiogenic agent, the therapeutic potential of FGF-2 in the ischemic myocardium is discussed.
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PMID:Biological activities of fibroblast growth factor-2 in the adult myocardium. 1250 9

Fibroblast growth factors (FGFs) are potent stimulators of angiogenesis in vitro and in vivo. However, the precise role of FGFs and vascular development in normal and pathological tissue has long remained ill defined. Recently, substantial progress has been made toward a better understanding of their role. Genetic studies in mice or in culture systems indicate a role for FGFs in vessel assembly and sprouting. FGFs also stimulate blood vessel branching and lymphangiogenesis. The molecular mechanisms by which FGFs mediate angiogenesis are also better understood. Finally, the FGF/FGF-receptor system has become a focus for the development of novel therapeutic strategies for the treatment of angiogenesis-related diseases such as tissue ischemia.
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PMID:Regulation of vascular development by fibroblast growth factors. 1285 9


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