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)

Intramyocardial injection of genes encoding angiogenic factors could provide a useful approach for the treatment of ischemic heart disease. However, uncontrolled expression of angiogenic factors in vivo may cause some unwanted side effects, such as hemangioma formation, retinopathy, and arthritis. It may also induce occult tumor growth and artherosclerotic plaque progression. Because hypoxia-inducible factor 1 is up-regulated in a variety of hypoxic conditions and it regulates gene expression by binding to a cis-acting hypoxia-responsive element (HRE), we propose to use HRE, found in the 3' end of the erythropoietin gene to control gene expression in ischemic myocardium. A concatemer of nine copies of the consensus sequence of HRE isolated from the erythropoietin enhancer was used to mediate hypoxia induction. We constructed two adeno-associated viral vectors in which LacZ and vascular endothelial growth factor (VEGF) expressions were controlled by this HRE concatemer and a minimal simian virus 40 promoter. Both LacZ and VEGF expression were induced by hypoxia and/or anoxia in several cell lines transduced with these vectors. The functions of these vectors in ischemic myocardium were tested by injecting them into normal and ischemic mouse myocardium created by occlusion of the left anterior descending coronary artery. The expression of LacZ gene was induced eight times and of VEGF 20 times in ischemic myocardium compared with normal myocardium after the viral vector transduction. Hence, HRE is a good candidate for the control of angiogenic factor gene expression in ischemic myocardium.
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PMID:Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model. 1208 14

Vascular development involves vasculogenesis, in which endothelial cells form a primary tubular network, as well as angiogenesis, in which vessel size and structure are modified based upon flow and branching occurs to insure that all cells receive adequate O2 delivery. In adults, angiogenesis occurs in response to tissue hypoxia/ischemia and plays an important role in determining the progression of ischemic heart disease and cancer. A critical molecular pathway induced by hypoxia/ischemia is the activation of hypoxia-inducible factor 1, a transcriptional activator of genes encoding vascular endothelial growth factor and other important mediators of angiogenesis. Novel therapeutic approaches that involve stimulating angiogenesis in ischemic tissue and inhibiting angiogenesis in neoplastic tissue are currently being evaluated in clinical trials.
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PMID:Angiogenesis in ischemic and neoplastic disorders. 1235 28

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular diseases, such as peripheral arterial disease, ischemic heart disease, 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 started in 1994 treating peripheral vascular disease with vascular endothelial growth factor (VEGF) and since then, many different potent angiogenic growth factors have been tested in clinical trials for the treatment of peripheral arterial disease. In addition, therapeutic angiogenesis using the VEGF gene has been used to treat ischemic heart disease since 1997. The results from these clinical trials have exceeded expectations; improvement in the clinical symptoms of peripheral arterial disease and ischemic heart disease has been reported. Another strategy for combating the disease processes, targeting the transcriptional process, has been tested in a human trial. IN particular, transfection of cis-element double-stranded (ds) oligodeoxynucleotides (ODN) (= decoy) is a powerful tool in a new class of anti-gene strategies. Transfection of ds-ODN corresponding to the cis sequence will attenuate the authentic cis-trans interaction, leading to removal of trans-factors from the endogenous cis-elements and subsequent modulation of gene expression. Genetically modified vein grafts transfected with a decoy against E2F, an essential transcription factor in cell cycle progression, appear to have long-term potency in human patients. There is great potential in gene therapy for cardiovascular disease.
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PMID:Recent progress in gene therapy for cardiovascular disease. 1249 10

Therapeutic angiogenesis is a promising treatment for ischaemic heart disease, particularly for patients who are not candidates for current methods of revascularisation. The goal of angiogenic therapy is the relief of symptoms of coronary artery disease and improvement of cardiac function by increasing perfusion to the ischaemic myocardium. Angiogenic cytokines such as fibroblast growth factor and vascular endothelial growth factor have been studied extensively in preclinical studies. Protein-based therapy with these growth factors has produced functionally significant angiogenesis in several animal models. Enthusiasm following these preclinical results led the way to clinical trials, which so far have shown only modest improvements in myocardial perfusion and clinical outcome. The attenuated angiogenic response to growth factor therapy observed in patients with coronary artery disease may be related to associated conditions such as endothelial dysfunction, regimens of single as opposed to multiple angiogenic agents and inefficiency of current delivery modalities, as illustrated by the disappointing results of the Phase II clinical trials using intravascular techniques of administration. The ultimate role angiogenesis will play clinically in the treatment of ischaemic heart disease will be determined by adequately powered, randomised, double-blind, placebo-controlled trials that include multi-agent angiogenic therapy and intramyocardial methods of delivery.
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PMID:Therapeutic angiogenesis: protein-based therapy for coronary artery disease. 1256 12

Angiogenesis, which is defined as the outgrowth of nutritive vessels from locally preexisting ones, is primarily based on the outgrowth of locally present endothelial cells and implies a delicate balance where both stimulating and inhibitory factors can influence the outcome. The primary players starting the process are the vascular endothelial growth factors (VEGFs), which stimulate endothelial cell growth, although some other key factors such as fibroblast growth factors (FGFs), placental growth factors (PIGFs), platelet-derived growth factors (PDGFs) and angiopoietins must come into play for vessels to mature and not deteriorate. Two possibilities exist in terms of local delivery of the angiogenic proteins. One is the delivery of the protein in a slow-release formulation. Fibrin or alginate formulations have been implanted, sub-epicardially releasing FGF. Another approach to get a local delivery over a period of time is gene therapy by local delivery of the vector carrying the therapeutic gene or with the development of vectors that are taken up and expressed only in the organ of interest. A transient overexpression, desirable for the treatment of ischemic heart disease, can be achieved with adenoviral vectors or naked plasmid. With VEGF gene transfection, angiogenesis and reendothelialization were demonstrated in animal cardiac ischemia models showing proof of principle for cardiac therapy and paving the way for clinical trials. Currently, about 200 patients have been treated with intramyocardial VEGF gene therapy for peripheral occlusive artery disease or for myocardial ischemia. Reported adverse events have been few and no worsening of atherosclerosis following treatment has been observed.
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PMID:Angiogenic gene therapy. 1258 71

The mechanisms underlying coronary capillary growth in response to ischemia are undefined. We hypothesized that the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)/Tie-2 were involved in capillary growth as an adaptation to ischemia. To test this hypothesis we measured capillary density, and the expressions of VEGF, Ang-1, Ang-2, and the Tie-2 receptor and its phosphorylation state during repetitive episodes of myocardial ischemia in chronically instrumented canines. Repetitive episodes of ischemia were induced by multiple (once/hour; 8/day), brief (2 min) occlusions of the left anterior descending coronary artery for 1, 7, 14, or 21 days. A sham group received the same instrumentation as the experimental groups but not the occlusion protocol. Collateral blood flow (microspheres) progressively increased from 9 +/- 3 to 83 +/- 10 ml. min-1. 100 g-1 on day 21. Capillary density increased at day 7 from 2378 +/- 53 (sham) to 2962 +/- 60/mm2, but it decreased to 2594 +/- 39/mm2 at day 21. Both VEGF and Ang-2 expression in myocardial interstitial fluid (Western analyses) peaked at day 3 of the repetitive occlusions but waned thereafter. In contrast the expression of Ang-1 remained relatively constant at all times in the occlusion groups. In shams, the expression of VEGF and Ang-2 was low and constant at all times. Tie-2 phosphorylation myocardial decreased decreased at day 7 but increased at 21 days of occlusions (P < 0.05). Our results indicate that capillary density was augmented by myocardial ischemia, but after development of collaterals and restoration of flow to the ischemic zone, capillary density returned to control levels. The change in capillary density paralleled with VEGF and Ang-2 expression but was inversely related to Tie-2 phosphorylation. We speculate the coronary angiogenesis is a coordinated event involving the expression of both VEGF and Ang-2 and that therapeutic angiogenic strategies may ultimately require treatment with more than a single factor.
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PMID:Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis. 1264 74

Gene therapy approaches involving vascular endothelial growth factor (VEGF) to promote therapeutic angiogenesis are under consideration for conditions ranging from ischemic heart disease to nonhealing skin ulcers. Here we make the surprising observation that the transgenic delivery of VEGF to the skin results in a profound inflammatory skin condition with many of the cellular and molecular features of psoriasis, including the characteristic vascular changes, epidermal alterations, and inflammatory infiltrates. Even longstanding psoriatic disease remains dependent on the transgenic VEGF in this model because it can be effectively reversed by the addition of VEGF Trap, a potent VEGF antagonist. Previous attempts to faithfully replicate the psoriatic phenotype through the transgenic delivery of epidermal keratinocyte growth factors or inflammatory mediators generated phenotypes with only partial resemblance to human psoriasis, leaving unanswered questions about the etiology of this disease. The ability of transgenic VEGF to induce a psoriasiform phenotype suggests a new etiology and treatment approach for this disease and further substantiates emerging concerns about possible proinflammatory adverse effects that might be associated with therapeutic attempts to deliver VEGF.
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PMID:Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. 1264 36

Cardiovascular atherosclerotic diseases remain leading causes of morbidity and mortality in the world. Despite the significant progress that has been made in the management of these diseases using medical, surgical and percutaneous therapies over the last three decades, there remains a significant population of patients who are not optimal candidates for surgical or percutaneous revascularization. Substantial research has focused on the administration of angiogenic growth factors, either as recombinant protein or by gene transfer, to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries; a strategy termed "therapeutic angiogenesis". While many cytokines have angiogenic activity, the best studied both in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). This review will discuss gene transfer strategies for therapeutic angiogenesis in critical limb and myocardial ischemia.
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PMID:Therapeutic angiogenesis by gene transfer in critical limb and myocardial ischemia. 1267 56

Increasing evidence suggests that postnatal neovascularization involves the recruitment of circulating endothelial progenitor cells (EPCs). Hematopoietic and endothelial cell lineages share common progenitors. Cytokines formerly thought to be specific for the hematopoietic system have only recently been shown to affect several functions in endothelial cells. Accordingly, we investigated the stimulatory potential of erythropoietin (Epo) on EPC mobilization and neovascularization. The bone marrow of Epo-treated mice showed a significant increase in number and proliferation of stem and progenitor cells as well as in colony-forming units. The number of isolated EPCs and CD34+/flk-1+ precursor cells was significantly increased in spleen and peripheral blood of Epo-treated mice compared with phosphate-buffered saline-treated mice. In in vivo models of postnatal neovascularization, Epo significantly increased inflammation- and ischemia-induced neovascularization. The physiologic relevance of these findings was investigated in patients with coronary heart disease. In a multivariate regression model, serum levels of Epo and vascular endothelial growth factor were significantly associated with the number of stem and progenitor cells in the bone marrow as well as with the number and function of circulating EPCs. In conclusion, the present study suggests that Epo stimulates postnatal neovascularization at least in part by enhancing EPC mobilization from the bone marrow. Epo appears to physiologically regulate EPC mobilization in patients with ischemic heart disease. Thus, Epo serum levels may help in identifying patients with impaired EPC recruitment capacity.
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PMID:Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. 1270 3

Angiopoietins are a recently discovered family of growth factors which act on endothelial cells via Tie receptors. They are widely expressed and have essential roles in regulating vascular growth, development, maturation and permeability. Disturbances in microvascular regulation play an important part in a number of diseases prominent in the developed world including diabetes, ischemic heart disease and cancer. It is the interplay between angiopoietins and other factors including vascular endothelial growth factor (VEGF) which determines endothelial behavior both in health and in these diseases. Angiopoietin-1 is unique in its ability to reduce endothelial permeability and it antagonises the effects of VEGF in its permeability and angiogenesis-inducing actions. The renal glomerulus constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. Disturbance of this function may cause a reduction in glomerular filtration rate or proteinuria. Understanding of the regulation of the filtration barrier is incomplete but the expression of angiopoietins in the glomerulus suggests a mechanism for maintenance of the glomerular endothelium and modulation of the actions of glomerular VEGF. As has been clearly shown for VEGF, angiopoietins are likely to be involved in glomerular disease and recovery from it. Manipulation of angiopoietins has a wide range of potential therapeutic applications from inhibition of diabetic retinal neovascularisation to promotion of glomerular repair.
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PMID:Angiopoietins: microvascular modulators with potential roles in glomerular pathophysiology. 1276 63


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