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)

Cell transplantation into hepatic sinusoids, which is necessary for liver repopulation, could cause hepatic ischemia. To examine the effects of cell transplantation on host hepatocytes, we transplanted Fisher 344 rat hepatocytes into syngeneic dipeptidyl peptidase IV-deficient rats. Within 24 h of cell transplantation, areas of ischemic necrosis, along with transient disruption of gap junctions, appeared in the liver. Moreover, host hepatocytes expressed gamma-glutamyl transpeptidase (GGT) extensively, which was observed even 2 years after cell transplantation. GGT expression was not associated with alpha-fetoprotein activation, which is present in progenitor cells. Increased GGT expression was apparent after transplantation of nonparenchymal cells and latex beads but not after injection of saline, fragmented hepatocytes, hepatocyte growth factor, or turpentine. Some host hepatocytes exhibited apoptosis, as well as DNA synthesis, between 24 and 48 h after cell transplantation. Changes in gap junctions, GGT expression, DNA synthesis, and apoptosis after cell transplantation were prevented by vasodilators. The findings indicated the onset of ischemic liver injury after cell transplantation. These hepatic perturbations must be considered when transplanted cells are utilized as reporters for biological studies.
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PMID:Cell transplantation causes loss of gap junctions and activates GGT expression permanently in host liver. 1100 70

Several studies have demonstrated an upregulation of endothelin-1 (ET-1) synthesis in acute and chronic renal failure. Epidermal growth factor (EGF) and hepatocyte growth factor (HGF) have been shown to stimulate renal tubular cell proliferation and to accelerate renal regeneration after drug-induced and ischemia-induced renal injury. This study aimed to investigate the effect of EGF and HGF on ET-1 release, and whether the effect of EGF and HGF is antagonized by the tyrosine kinase inhibitor lavendustin A. Rabbit proximal tubule cells were incubated for 48 h with EGF or HGF (0.1-10.0 nM), lavendustin A (0.1-10.0 microM) or co-incubated with EGF or HGF (1 nM) and lavendustin A. ET-1 concentrations in the culture medium were measured with a specific enzyme-linked immunosorbent assay (ELISA). EGF and HGF exerted a significant (p < 0.001) dose-dependent inhibitory effect on ET-1 release. Lavendustin A induced a dose-dependent stimulation of ET-1 release and antagonized the inhibitory effect of EGF and HGF on ET-1 release. The inhibition of EGF and HGF receptor tyrosine kinase activity by lavendustin A was confirmed by Western blotting. These data suggest that EGF and HGF reduce ET-1 release via EGF and HGF receptor tyrosine kinase activity. The inhibitory action of EGF and HGF on ET-1 release might be involved in mediating the protective effects of EGF and HGF in renal injury.
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PMID:Inhibitory effect of epidermal growth factor and hepatocyte growth factor on endothelin-1 release by rabbit proximal tubule cells. 1107 89

In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e., tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value
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PMID:Hepatocyte growth factor receptor in acute tubular necrosis. 1118 1

Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells, and acts as a survival factor against endothelial cell death. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. We have previously reported that intra-arterial administration of recombinant HGF induced angiogenesis in a rabbit hindlimb ischemia model. In this study, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease rather than recombinant therapy, due to its disadvantages. Initially, we examined the transfection of 'naked' human HGF plasmid into a rat hindlimb ischemia model. Intramuscular injection of human HGF plasmid resulted in a significant increase in blood flow as assessed by laser Doppler imaging, accompanied by the detection of human HGF protein. A significant increase in capillary density was found in rats transfected with human HGF as compared with control vector, in a dose-dependent manner (P < 0.01). Importantly, at 5 weeks after transfection, the degree of angiogenesis induced by transfection of HGF plasmid was significantly greater than that caused by a single injection of recombinant HGF. As an approach to human gene therapy, we also employed a rabbit hindlimb ischemia model as a preclinical study. Naked HGF plasmid was intramuscularly injected in the ischemic hindlimb of rabbits, to evaluate its angiogenic activity. Intramuscular injection of HGF plasmid once on day 10 after surgery produced significant augmentation of collateral vessel development on day 30 in the ischemia model, as assessed by angiography (P < 0.01). Serial angiograms revealed progressive linear extension of collateral arteries from the origin stem artery to the distal point of the reconstituted parent vessel in HGF-transfected animals. In addition, a significant increase in blood flow was assessed by a Doppler flow wire and the ratio in blood pressure of the ischemic limb to the normal limb was observed in rabbits transfected with HGF plasmid as compared with rabbits transfected with control vector (P < 0.01). Overall, intramuscular injection of naked human HGF plasmid induced therapeutic angiogenesis in rat and rabbit ischemic hindlimb models, as potential therapy for peripheral arterial disease.
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PMID:Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease. 1131 89

Hepatocyte growth factor (HGF) has been shown to enhance recovery from renal tubular ischemia. We investigated the possibility that HGF improves recovery by preventing ischemia-induced loss of cell adhesion. Murine inner medullary collecting duct-3 (mIMCD-3) cells subjected to 90% ATP depletion demonstrated a 55% decrease in adhesion, an effect that was completely reversed by the addition of HGF. Assays examining release of adherent cells revealed similar results with 30 min of ATP depletion causing loss of adhesion of 25% of mIMCD-3 cells and HGF completely reversing this effect. In contrast, HGF was unable to reverse the loss of adhesion of cells exposed to 99% ATP depletion. Examination of the mitogen-activated protein kinase (MAPK) signaling pathway revealed that HGF could induce extracellular signal-regulated kinase (ERK) phosphorylation in control and 90% ATP-depleted cells but not in 99% ATP-depleted cells. Inhibition of ERK activation with U0126 completely blocked the HGF-dependent reversal of ATP-depleted cell adhesion. Thus ATP-depleted cells demonstrate a marked decrease in cell adhesion that is reversible by the addition of HGF. This effect of HGF requires activation of the MAPK pathway.
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PMID:HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner. 1139 47

Recent progress in molecular biology has led to the development of gene therapy as a new strategy to treat a variety of cardiovascular diseases. Targeted diseases range from single gene deficiency diseases to more complex diseases in adults such as restenosis after angioplasty. One obvious major target in the field of gene therapy is ischemic diseases such as myocardial infarction, angina and peripheral arterial diseases (i.e. ASO (arteriosclerosis obliterans)). In a large proportion of such patients, the anatomical extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. Of importance, there is no optimal medical therapy for severe ischemic hearts and critical ischemic limbs. Therefore, novel therapies are required to treat these patients. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia and myocardial ischemia. Thus, the strategy for therapeutic angiogenesis using angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. The endothelial cell specificity of VEGF has been considered to be an important advantage for therapeutic angiogenesis, as endothelial cells represent the critical cellular element responsible for new vessel formation. Indeed, human gene therapy for ASO and angina has already begun in the USA, with surprising and beneficial effects. We have focused on hepatocyte growth factor (HGF), which is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis in various types of cells. Recently, HGF is also considered to be a powertul growth tactor for endothelial cells. In this review, we described the potential gene therapy for ischemic diseases using HGF.
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PMID:Therapeutic angiogenesis induced by hepatocyte growth factor: potential gene therapy for ischemic diseases. 1142 85

Hepatocyte growth factor (HGF) was originally discovered as a powerful mitogen for hepatocytes. HGF also has been reported to function as a neurotrophic factor as well as an angiogenetic factor. The present study examined the neuroprotective effect of HGF against transient focal cerebral ischemia in rats, in which an anti-apoptotic and an angiogenetic effect of HGF was assumed to contribute to the reduction of the infarct volume. The intraventricular administration of human recombinant HGF prevented neuronal death after 120 min of occlusion in the right middle cerebral artery and the bilateral common carotid arteries. HGF significantly reduced the infarct volume in a dose-dependent manner. In a separate series of experiments, we next histopathologically investigated both the anti-apoptotic effect on neurons and the angiogenetic effect of HGF. A large number of TUNEL positive neurons were observed in the inner boundary of the infarct area in both the control and the vehicle group whereas only a few TUNEL positive neurons were observed in the corresponding area in the HGF group. In the HGF group, Bcl-2 protein was obviously represented in surviving neurons subjected to ischemia. The number of the vascular lamina in HGF group were significantly higher than those in the vehicle group. These data suggest that HGF appears to have an ability to prevent apoptotic neuronal cell death while also possessing an angiogenetic effect in the central nervous system which was affected with transient focal cerebral ischemia.
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PMID:Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats. 1142 24

Hepatocyte growth factor (HGF) was originally discovered as a powerful mitogen for hepatocytes. HGF functions both as a neurotrophic factor as well as an angiogenetic factor. Furthermore, HGF has an anti-apoptotic effect on vascular endothelial cells. The present study examined the neuroprotective effect of HGF after transient focal cerebral ischemia in rats, in which an anti-apoptotic and an angiogenetic effect of HGF was assumed to contribute to the reduction of the infarct volume. The intraventricular administration of human recombinant HGF (90 micrograms) significantly reduced the infarct volume after 120 minutes occlusion of both the right middle cerebral artery (MCA) and the bilateral common carotid arteries (CCAs). In a separate series of experiments, we investigated both the anti-apoptotic effect on neurons and the angiogenetic effect of HGF histopathologically. The number of survival neurons and vascular lumina in the HGF group were significantly higher than those in the vehicle group. A large number of TUNEL positive neurons were observed in the inner boundary of the infarct area in the vehicle group, whereas only a few TUNEL positive neurons were observed in a corresponding area in the HGF group. In the HGF group, Bcl-2 protein was obviously represented in survival neurons as well as in vascular endothelial cells and in glial cells subjected to ischemia. These data suggest that HGF prevents apoptotic neuronal cell death by upregulating the production of Bcl-2 protein and by an angiogenetic effect in the central nervous system which affected transient focal cerebral ischemia.
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PMID:Hepatocyte growth factor reduces infarct volume after transient focal cerebral ischemia in rats. 1145 33

To develop a novel strategy to prevent delayed neuronal death (DND) following transient occlusion of arteries, the gene of hepatocyte growth factor (HGF), a novel neurotrophic factor, was transfected into the subarachnoid space of gerbils after transient forebrain ischemia. Importantly, transfection of HGF gene into the subarachnoid space prevented DND, accompanied by a significant increase in HGF in the cerebrospinal fluid. Prevention of DND by HGF is due to the inhibition of apoptosis through the blockade of bax translocation from the cytoplasm to the nucleus. HGF gene transfer into the subarachnoid space may provide a new therapeutic strategy for cerebrovascular disease.
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PMID:Gene therapy for preventing neuronal death using hepatocyte growth factor: in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons. 1150 47

Although clinical trials of stimulation of angiogenesis by transfection of angiogenic growth factors using naked plasmid DNA or adenoviral vector have been successful, there are still unresolved problems for human gene therapy such as low transfection efficiency and safety. From this viewpoint, it is necessary to develop safe and efficient novel nonviral gene transfer methods. As therapeutic ultrasound induces cell membrane permeabilization, ultrasound irradiation might increase the transfection efficiency of naked plasmid DNA into skeletal muscle. Thus, we examined the transfection efficiency of naked plasmid DNA using ultrasound irradiation with echo contrast microbubble (Optison) in vitro and in vivo experiments. First, we examined the feasibility of ultrasound-mediated transfection of naked plasmid DNA into skeletal muscle cells. Luciferase plasmid mixed with or without Optison was transfected into cultured human skeletal muscle cells using ultrasound (1 MHz; 0.4 W(2)) for 30 s. Interestingly, luciferase activity was markedly increased in cells treated with Optison, while little luciferase activity could be detected without Optison (P < 0.01). Electron microscopy demonstrated the transient formation of holes (less than 5 microM) in the cell surface, which could possibly explain the rapid migration of the transgene into the cells. Next, we studied the in vivo transfection efficiency of naked plasmid DNA using ultrasound with Optison into skeletal muscle. Two days after transfection, luciferase activity in skeletal muscle transfected with Optison using ultrasound was significantly increased about 10-fold as compared with plasmid alone. Successful transfection was also confirmed by beta-galactosidase staining. Finally, we examined the feasibility of therapeutic angiogenesis using naked hepatocyte growth factor (HGF) plasmid in a rabbit ischemia model using the ultrasound-Optison method. Five weeks after transfection, the angiographic score and the number of capillary density in rabbits transfected with Optison using ultrasound was significantly increased as compared with HGF plasmid alone (P < 0.01), accompanied by a significant increase in blood flow and blood pressure ratio (P < 0.01). Overall, the ultrasound transfection method with Optison enhanced the transfection efficiency of naked plasmid DNA in vivo as well as in vitro. Transfection of HGF plasmid by the ultrasound-Optison method could be useful for safe clinical gene therapy to treat peripheral arterial disease without a viral vector system.
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PMID:Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle. 1196 Mar 13


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