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)

The expression of vascular endothelial growth factor (VEGF) in the model of rat early acute myocardial ischemia was studied by Strept-Avidin-Biotin-Peroxidase Complex (SABC) immunohistochemical staining. After ligating the anterior descending branch of the left coronary artery, an initial rapid (30min) positive expression of VEGF in myocardial ischemic areas was observed, the intensity of positive expression of VEGF increased with the continuation of myocardial ischemia. After 5h infarction, the strongly positive myocytes of SABC-VEGF staining were predominantly limited to perimyocardial infarction areas. No positive expression of VEGF was found in the control group. These findings suggested that SABC-VEGF method could give a sensitive, specific, simple and objective morphologic evidence to the diagnosis of sudden cardiac death caused by acute early myocardial ischemia.
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PMID:Primary study of vascular endothelial growth factor immunohistochemical staining in the diagnosis of early acute myocardial ischemia. 1134 49

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 angiogenesis based on the administration of growth factors with angiogenic activity allows enhancement of collateral vessels able to palliate insufficient tissue perfusion secondary to obstruction of native arteries. At present, this type of therapy is addressed to patients that fail to respond to conventional treatment (surgical or percutaneous revascularization). The most extensively investigated angiogenic growth factors are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). These cytokines can be administered either as recombinant proteins or as the genes encoding for these proteins. Both approaches have pros and cons that are under investigation in animal models and in clinical studies. Although clinical trials consist so far of small, often non-randomized series, preliminary results are promising. For example, administration of VEGF or FGF has been associated to objective evidence of increased tissue perfusion in patients with myocardial ischemia, and to a significant improvement of pain and ischemia in patients with peripheral arterial disease. Contrarily to expected, these interventions have been associated to scant adverse side effects, although larger clinical trials will be necessary in order to prove the safety and effectiveness of these interventions. Nevertheless, it seems clear that it is feasible to induce effective therapeutic angiogenesis in selected patients without significant associated toxicity.
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PMID:[Growth factors for therapeutic angiogenesis in cardiovascular diseases]. 1159 2

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or antisense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.
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PMID:Gene therapy for cardiovascular disease: a case for cautious optimism. 1171 25

Angiogenesis is the process of new blood vessel formation, and has potential clinical use in the management of ischemic heart disease. A considerable amount of ongoing research has recently focused on the process of angiogenesis, including the identification of various factors that can inhibit or stimulate this process. The picture that is emerging suggests that a complex set of interactions involving various cells and cellular products is the key to angiogenesis. In particular, endothelial cells and growth factors, such as vascular endothelial growth factor and fibroblast growth factor, appear to play integral roles in angiogenesis. Various preclinical studies involving animal models of ischemia explored the potential use of angiogenesis in ischemic disease. Based on encouraging results, a number of clinical trials involving angiogenesis have been initiated to determine whether the process of angiogenesis also offers therapeutic benefit in humans.
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PMID:Therapeutic angiogenesis: a new treatment modality for ischemic heart disease. 1172 75

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular diseases, such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy, for which no known effective therapy exists. The first human trial in cardiovascular disease was started in 1994 to treat peripheral vascular disease using vascular endothelial growth factor. In addition, therapeutic angiogenesis using the vascular endothelial growth factor gene was applied in the treatment of ischemic heart disease. The results from these clinical trials seem to exceed expectation. Improvement of clinical symptoms in peripheral arterial disease and ischemic heart disease has been reported. At least five different potent angiogenic growth factors have been tested in clinical trials to treat peripheral arterial disease or ischemic heart disease. In addition, another strategy for combating disease processes, to target the transcriptional process, has been tested in a human trial. Transfection of cis-element double-stranded oligodeoxynucleotides is an especially powerful tool in a new class of antigen strategies for gene therapy. Transfection of double-stranded oligodeoxynucleotides corresponding to the cis sequence will result in the attenuation of the authentic cis-trans interaction, leading to the removal of trans-factors from the endogenous cis-elements, with subsequent modulation of gene expression. Genetically modified vein grafts transfected with a decoy against E2F, an essential transcription factor in cell cycle progression, revealed apparent long-term potency in human patients. This review focuses on the future potential of gene therapy for the treatment of cardiovascular disease.
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PMID:Gene therapy in vascular medicine: recent advances and future perspectives. 1172 4

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

This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials. Evidence for the use of gene therapy to limit neointimal hyperplasia and confer myocardial protection was presented, and it was found that augmenting local nitric oxide (NO) production using gene transfer (GT) of NO synthase or interruption of cell cycle progression through a genetic transfer of cell cycle regulatory genes limited vascular smooth muscle hyperplasia in animal models and infra-inguinal bypass patients. The results of application of vascular endothelial growth factor (VEGF) GT strategies for therapeutic angiogenesis in critical limb and myocardial ischemia in pilot clinical trials was reviewed. In addition, experimental evidence was presented that genetic manipulation of peptide systems (i.e., the renin-angiotensin II system and the kallikrein-kinin system) was effective in the treatment of systemic cardiovascular diseases such as hypertension, heart failure, and renal failure. Although, as of yet, there are no well controlled human trials proving the clinical benefits of gene therapy for cardiovascular diseases, the data presented here in animal models and in human subjects show that genetic targeting is a promising and encouraging modality, not only for the treatment and long-term control of cardiovascular diseases, but for their prevention as well.
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PMID:Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? 1177 94

Recent studies suggest that the HMG-CoA reductase inhibitor simvastatin--similar to vascular endothelial growth factor (VEGF)--may promote angiogenesis by activation of a protein kinase Akt-nitric oxide synthase dependent pathway in endothelial cells, an effect that may be beneficial in the treatment of ischemic heart disease. However, induction of angiogenesis by VEGF contributes importantly to the blood supply of developing tumors and tumor metastases as well. Thus, it can be hypothesized that chronic systemic treatment of elderly patients with a drug that induces angiogenesis by a VEGF-like manner will also promote tumor growth.
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PMID:Can simvastatin promote tumor growth by inducing angiogenesis similar to VEGF? 1186 4

A modern experimental strategy for treating myocardial ischemia is to induce neovascularization of the heart by the use of "angiogens", mediators that induce the formation of blood vessels, or angiogenesis. Studies demonstrated that coronary collateral vessels protect ischemic myocardium after coronary obstruction; therefore we sought to examine a novel method of stimulating myocardial angiogenesis through hypoxic preconditioning at both capillary (using anti-CD31) and arteriolar (using anti- alpha smooth muscle actin) levels and also investigate whether such treatments could preserve left ventricular contractile functional reserve and regional blood flow by increasing vascular endothelial growth factor (VEGF). Male Sprague-Dawley rats were randomly divided into four groups: normoxia+sham surgery (CS), normoxia+permanent left anterior descending coronary artery (LAD) occlusion (CMI), hypoxic preconditioning+sham surgery (HS) and hypoxic preconditioning+permanent LAD occlusion (HMI). Rats in the preconditioned groups were subjected to systemic hypoxemic hypoxic exposure (10+/-0.4% O(2)) for 4 h followed by a 24 h period of normoxic reoxygenation prior to undergoing LAD occlusion. Rats in the normoxia group were time matched with the preconditioned group and maintained under normoxic conditions for a 28 h period prior to LAD occlusion. Western blot analysis was performed to measure VEGF expression and TUNEL staining with endothelial cell-specific antibody, anti-VWF, was used to examine endothelial apoptosis. One, two and three weeks after the LAD occlusion, baseline left ventricular pressures were monitored and recorded. Pharmacological stress tests with dobutamine infusion in progressively increasing doses revealed significantly elevated contractile reserve at each dose point in the HMI group compared to the CMI group. The HMI group displayed statistically significant increases in capillary as well as arteriolar density after 1, 2 and 3 weeks post-operation. Blood flow was also significantly elevated in the HMI groups when compared to the CMI group. The extent of endothelial cell apoptosis was found to be inversely proportional to VEGF expression. It was concluded that hypoxic preconditioning stimulates myocardial angiogenesis to an extent sufficient to exert significant cardioprotection in a rat model of myocardial infarction progressing to heart failure as evidenced by increased capillary/arteriolar density and enhanced ventricular contractile functional reserve.
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PMID:Hypoxic preconditioning triggers myocardial angiogenesis: a novel approach to enhance contractile functional reserve in rat with myocardial infarction. 1194 25


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