Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, vascular endothelial growth factor-C (VEGF-C or VEGF-2) was described as a specific ligand for the endothelial receptor tyrosine kinases VEGFR-2 and VEGFR-3. In vivo data, limited to constitutive overexpression in transgenic mice, have been interpreted as evidence that the growth-promoting effects of VEGF-C are restricted to development of the lymphatic vasculature. The current studies were designed to test the hypothesis that constitutive expression of VEGF-C in adult animals promotes angiogenesis. In vitro, VEGF-C exhibited a dose-dependent mitogenic and chemotactic effect on endothelial cells, particularly for microvascular endothelial cells (72% and 95% potency, respectively, compared with VEGF-A/VEGF-1). VEGF-C stimulated release of nitric oxide from endothelial cells and increased vascular permeability in the Miles assay; the latter effect was attenuated by pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester. Both VEGFR-2 and VEGFR-3 receptors were shown to be expressed in human saphenous vein and internal mammary artery. The potential for VEGF-C to promote angiogenesis in vivo was then tested in a rabbit ischemic hindlimb model. Ten days after ligation of the external iliac artery, VEGF-C was administered as naked plasmid DNA (pcVEGF-C; 500 microg) from the polymer coating of an angioplasty balloon (n = 8 each) or as recombinant human protein (rhVEGF-C; 500 microg) by direct intra-arterial infusion. Physiological and anatomical assessments of angiogenesis 30 days later showed evidence of therapeutic angiogenesis for both pcVEGF-C and rhVEGF-C. Hindlimb blood pressure ratio (ischemic/normal) after pcVEGF-C increased to 0.83 +/- 0.03 after pcVEGF-C versus 0.59 +/- 0.04 (P < 0.005) in pGSVLacZ controls and to 0.76 +/- 0.04 after rhVEGF-C versus 0.58 +/- 0.03 (P < 0.01) in control rabbits receiving rabbit serum albumin. Doppler-derived iliac flow reserve was 2.7 +/- 0.1 versus 2.0 +/- 0.2 (P < 0.05) for pcVEGF-C versus LacZ controls and 2.9 +/- 0.3 versus 2.1 +/- 0.2 (P < 0.05) for rhVEGF-C versus albumin controls. Neovascularity was documented by angiography in vivo (angiographic scores: 0.85 +/- 0.05 versus 0.51 +/- 0.02 (P < 0.001) for plasmid DNA and 0.74 +/- 0.08 versus 0.53 +/- 0.03 (P < 0.05) for protein), and capillary density (per mm2) was measured at necropsy (252 +/- 12 versus 183 +/- 10 (P < 0.005) for plasmid DNA and 229 +/- 20 versus 164 +/- 20 (P < 0.05) for protein). In contrast to the results of gene targeting experiments, constitutive expression of VEGF-C in adult animals promotes angiogenesis in the setting of limb ischemia. VEGF-C and its receptors thus constitute an apparently redundant pathway for postnatal angiogenesis and may represent an alternative to VEGF-A for strategies of therapeutic angiogenesis in patients with limb and/or myocardial ischemia.
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PMID:Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. 970 99

A gene therapy strategy involving direct myocardial administration of an adenovirus (Ad) vector encoding the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) has been shown to be capable of "biological revascularization" of ischemic myocardium in an established porcine model [Mack, C.A. (1998). J. Thorac. Cardiovasc. Surg. 115, 168-177]. The present study evaluates the local and systemic safety of this therapy in this porcine ischemia model and in normal mice. Myocardial ischemia was induced in Yorkshire swine with an ameroid constrictor 21 days prior to vector administration. Ad(GV)VEGF121.10 (10(9) or 10(10) PFU), Ad5 wild type (10(9) PFU), AdNull (control vector with no transgene; 10(9) PFU), saline, or no injection (naive) was administered in 10 sites in the ischemic, circumflex distribution of the myocardium. Toxicity was assessed by survival, serial echocardiography, blood analyses, and myocardial and liver histology at 3 and 28 days after vector administration. All pigs survived to sacrifice, except for one animal in the Ad(GV)VEGF121.10 (10(10) PFU) group, which died as a result of oversedation. Echocardiograms of Ad(GV)VEGF121.10-treated pigs demonstrated no differences in pericardial effusion, mitral valve regurgitation, or regional wall motion compared with control pigs. Intramyocardial administration of Ad(GV)VEGF121.10 included only minimal myocardial inflammation and necrosis, and no hepatic inflammation or necrosis. Only a mild elevation of the white blood cell count was encountered on day 3, which was transient and self-limited in the Ad(GV)VEGF121.10 group as compared with the saline-treated animals. As a measure of inadvertent intravascular administration of vector, normal C57/BL6 mice received intravenous Ad(GV)VEGF121.10 (10(4), 10(6), 5 x 10(7), or 10(9) PFU), AdNull (5 x 10(7) or 10(9) PFU), or saline. Toxicity was assessed by survival, blood analyses, and organ histology at 3 and 7 days after vector administration. A separate group of C57/BL6 mice received intravenous AdmVEGF164 (Ad vector encoding the murine VEGF164 cDNA), Ad(GV)VEGF121.10, AdNull (10(8) PFU each group), or saline to assess duration of expression and safety of a homologous transgene. All mice survived to sacrifice except for 40% of the mice in the highest (10(9) PFU; a dose more than 10(3)-fold higher by body weight than the efficacious dose in pigs) Ad(GV)VEGF121.10 dose group, which died on days 5-6 after vector administration. The only differences seen in the blood analyses between treated and control mice were in the very high Ad(GV)VEGF121.10 dose group (10(9) PFU), which demonstrated an anemia as well as an increase in alkaline phosphatase when compared with all other treatment groups. Hepatic VEGF levels by ELISA in AdmVEGF164-treated mice did not persist beyond 14 days after vector administration, suggesting that persistent expression of a homologous VEGF gene transferred with an Ad vector is not a significant safety risk. Although this is not a chronic toxicity study, these data demonstrate the safety of direct myocardial administration of Ad(GV)VEGF121.10, and support the potential use of this strategy to treat human myocardial ischemia.
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PMID:Safety of direct myocardial administration of an adenovirus vector encoding vascular endothelial growth factor 121. 1036 64

Both VEGF protein and VEGF DNA in combination with an adenoviral vector have been shown to enhance collateral formation in a porcine model of chronic myocardial ischemia. We sought to determine whether direct intramyocardial injection of naked DNA encoding for VEGF could similarly improve myocardial perfusion. Initially, 23 nonischemic pigs received either 200 microg of plasmid DNA encoding beta-galactosidase (pCMVbeta, n = 11) or 500 microg of phVEGF165 (n = 12) into four separate sites in the myocardium via a small anterolateral thoracotomy incision in the fourth intercostal space. Two additional groups of pigs received an intramyocardial injection of either phVEGF165 (n = 6) or pCMVbeta (n = 7) 3 to 4 weeks after implantation of an ameroid constrictor around the left circumflex coronary artery. The injections caused no change in heart rate or blood pressure, and no ventricular arrhythmias or histologic evidence of inflammation. VEGF protein was detected by Western blot in VEGF-treated animals, with the strongest bands closest to the injection site. Plasma VEGF concentration (ELISA) increased from 3+/-2 to 27+/-13 pg/ml (p = 0.035) by day 4 after treatment. No increase in VEGF protein was noted in pCMVbeta-treated animals whereas these did stain positive for beta-Gal. Resting myocardial blood flow (colored microspheres) was significantly reduced in the ischemic versus nonischemic territory in control animals (1.07+/-0.05 versus 1.32+/-0.05; p < 0.05) but not VEGF-treated pigs (1.32+/-0.24 versus 1.13+/-0.12; p = NS). Maximal vasodilatation with adenosine significantly increased flow to the ischemic region in VEGF-treated pigs (2.16+/-0.57 versus 1.32+/-0.24; p < 0.05) but not controls (1.31+/-0.05 versus 1.17+/-0.06;p = NS). Collateral filling of the occluded circumflex artery improved in five of six VEGF-treated pigs (mean change in Rentrop score, +1.5). We conclude that direct intramyocardial transfection phVEGF165 is safe and capable of producing sufficient VEGF protein to enhance collateral formation and myocardial perfusion. This approach may offer an alternative therapy for patients with intractable myocardial ischemia not amenable to PTCA or CABG.
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PMID:Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium. 1060 56

Angiogenic growth factors and their endothelial receptors function as major regulators of blood vessel formation. The VEGF/VEGFR and the Angiopoietin/Tie2 receptor systems represent key signal transduction pathways involved in the regulation of embryonic vascular development. Inactivation of any of the genes encoding these molecules results in defective vascular development and lethality between embryonic day 8.5 and 12.5. In addition, VEGF and its receptors are also critically involved in the regulation of pathological blood vessel growth in the adult during various angiogenesis-dependent diseases that are associated with tissue hypoxia, such as solid tumor growth and ischemic diseases. It is now well established that therapeutic angiogenesis can be achieved in animal models of hind limb and myocardial ischemia by exogenously adding VEGF and/or other angiogenic growth factors. Available clinical data from human trials also suggests that patients with severe cardiovascular diseases could potentially benefit from such therapies. However, much more work needs to be done to compare the potency of different angiogenic factors or the combination thereof, as well as the best way of delivery, either as recombinant proteins, as naked DNA or via adenoviral vectors. Nevertheless, the therapeutic efficacy of simply injecting naked plasmid DNA or proteins into ischemic tissue to deliver secreted angiogenic factors is an encouraging finding. Time will show whether the adverse side effects of therapeutic angiogenesis, mainly vascular permeability and edema formation, can be minimized and angiogenic factors can be used as an effective therapy in patients for the treatment of ischemic diseases such as arterial occlusive disease, myocardial infarction, and, eventually, also stroke.
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PMID:Angiogenesis in ischemic disease. 1069 85

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

Therapeutic myocardial angiogenesis by means of transient overexpression of angiogenic growth factors is a potential treatment modality for severe ischemic heart disease. This study was undertaken in the rat to examine effects of phVEGF-A(165) myocardial transfection in terms of dose-response as regards the number of hVEGF-A expressing cells on one hand and on the other angiogenesis. Non-surgical echocardiography-guided intramyocardial injection of phVEGF-A(165) was done into normoxic or hypoxic (10% O(2)) rats. Cardiomyocytes expressing VEGF-A protein, capillary morphology and density were determined after 5 days. VEGF protein expression was seen in rat cardiomyocytes located around the tip of the injection scar and increased dose-dependently (p<0.05). Microvessel density also increased dose-dependently with phVEGF(165) (p<0.05) and with hypoxia (p<0.05). No vascular tumours were observed. In conclusion, direct intramyocardial injection of phVEGF-A(165) in the rat results in a dose-dependent increase both in transfected hVEGF-A protein producing cells and in angiogenesis.
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PMID:Protein and angiogenic dose-response expression of phVEGF-A(165) gene in rat myocardium. 1172 66

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

Erythropoietin (Epo) is a hormone regulating proliferation and differentiation of erythroid cells. The hypothesis that hematopoietic and endothelial cells share a common hemangioblast progenitor among others is based on the finding that both cell lineages express cell surface antigens like CD31 and CD34. In this study we investigated the angiogenic potential of recombinant human erythropoietin (rHuEpo) on endothelial cells derived from human adult myocardial tissue. In addition, we compared the angiogenic potential of rHuEpo to that of other cytokines (VEGF, aFGF) and combinations of growth factors. Samples of myocardial tissue (cardiac auricle) were obtained during coronary bypass surgery, embedded in a fibrin gel matrix, and cultured for 21 days. Capillary sprouting was measured with an eye-piece graticule under an inverted-phase contrast microscope. Tube-forming endothelial cells were characterized by immunohistochemistry and RT-PCR. Using a concentration of 2.5 U/ml, we found that rHuEpo stimulates capillary outgrowth up to 220%, compared to the nonstimulated physiological outgrowth. Epo therefore exhibits the same angiogenic potential on endothelial cells in our in vitro assay as VEGF(165) (230% increase). Erythropoietin stimulates capillary outgrowth in an in vitro angiogenesis assay using adult human myocardial tissue. This implies a role of erythropoietin in vasoproliferative processes. rHuEpo may serve as a direct angiogenic substance in patients with ischemic heart disease.
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PMID:Erythropoietin and VEGF exhibit equal angiogenic potential. 1220 56

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease, for which no known effective therapy exists. The first human trial in cardiovascular disease was started in 1994 to treat peripheral vascular disease using VEGF. Since then, at least 5 different potent angiogenic growth factors has been tested in clinical trials to treat peripheral arterial disease. In addition, therapeutic angiogenesis using VEGF gene was applied to treat ischemic heart disease. Results from these clinical trials seems to be more than expected. Improvement of clinical symptoms in peripheral arterial disease or ischemic heart disease has been reported. In this review, we have focused on the future potential of gene therapy for the treatment of cardiovascular disease as a new pharmacological therapy.
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PMID:[Gene therapy in cardiovascular medicine as new pharmacological therapy]. 1242 47

Therapeutic angiogenesis may be a realistic approach in treating ischemic heart disease. VEGF is a major angiogenic factor involved in physiological as well as pathological angiogenesis. The ability of VEGF to promote angiogenesis in animal and clinical studies has been studied extensively. However, it is becoming clear that VEGF alone may not be sufficient to effectively complete the angiogenesis process. The use of more than one growth factor may be more pertinent in creating a sustainable angiogenic effect with clinically significant outcome. The challenge is to find complementary partners in angiogenesis to better affect the outcome of the process. To this end, we have been studying the effects of other angiogenic factors such as angiopoietin-1 (Ang-1) in a chronic ischemic porcine model. Single intramyocardial introduction of adenovirus-mediated gene transfer of Ang-1 into the left ventricle free wall has been found to enhance angiogenesis by augmenting the formation of new capillaries that manifested in improved total blood flow in the myocardium. A combined therapeutic angiogenesis study involving VEGF and Ang-1 is currently underway. Due to their unique complementary properties, it is expected that the combination will not merely enhance angiogenesis but will also lead to healthy and mature vascular network in the ischemic myocardium.
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PMID:Therapeutic angiogenesis for coronary artery disease. 1254 86


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