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)

Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice (Vegfb(-/-)). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile. Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis.
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PMID:Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. 1066 23

Blood vessels are among the easiest targets for gene therapy. However, no data are available about the safety and feasibility of intracoronary gene transfer in humans. We studied the safety and efficacy of catheter-mediated vascular endothelial growth factor (VEGF) plasmid/liposome (P/L) gene transfer in human coronary arteries after percutaneous translumenal coronary angioplasty (PTCA) in a randomized, double-blinded, placebo-controlled study. The optimized angioplasty/gene delivery method was previously shown to lead to detectable VEGF gene expression in human peripheral arteries as analyzed from amputated leg samples. Gene transfer to coronary arteries was done with a perfusion-infusion catheter, using 1000 microg of VEGF or beta-galactosidase plasmid complexed with 1000 microl of DOTMA:DOPE liposomes. Ten patients received VEGF P/L, three patients received beta-galactosidase P/L, and two patients received Ringer lactate. Gene transfer to coronary arteries was feasible and well tolerated. Except for a slight increase in serum C-reative protein in all study groups, no adverse effects or abnormalities in laboratory parameters were detected. No VEGF plasmid or recombinant VEGF protein was present in the systemic circulation after the gene transfer. In control angiography 6 months later, no differences were detected in the degree of coronary stenosis between treatment and control groups. We conclude that catheter-mediated intracoronary gene transfer performed after angioplasty is safe and well tolerated and potentially applicable for the prevention of restenosis and myocardial ischemia.
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PMID:Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty. 1068 Aug 40

Vascular endothelial growth factor (VEGF) was discovered 10 years ago as a growth factor that can regulate angiogenesis and in addition the permeability of blood vessels. Numerous studies have revealed that it is essential for normal embryonic development and that it plays a major role in physiological and pathological events of angiogenesis in adults. It is unique in that its expression is regulated directly by hypoxia. These properties are now being exploited in attempts aimed at the induction of new blood vessels in pathological situations such as ischemic heart disease. Five VEGF forms of 121 to 206 aminoacids are produced from a single gene by alternative splicing. Cells expressing VEGF usually express several forms simultaneously. VEGF121 does not contain exons 6 and 7 of the gene and consequently lacks a heparin binding ability. However, this form is fully active as an inducer of angiogenesis, and as a blood vessel permeabilizing agent. Exon 6 and 7 contain 2 independent heparin binding domains. The VEGF form containing exon 7 (VEGF165) and the vascular endothelial growth factor form containing exon 6 (VEGF145) display similar biological potencies raising the question of why so many VEGF forms are required. It was found that VEGF121 diffuses better because it does not bind to heparan-sulfate proteoglycans. In contrast, VEGF145 binds to extracellular matrix and is released from it slowly. When the receptor binding properties of VEGF121 and VEGF165 were compared it was found that VEGF165 binds to a class of VEGF receptors that is not recognized by VEGF121. These receptors are encoded by the neuropilin-1 gene, and we have recently found that the related neuropilin-2 gene also encodes a VEGF165 receptor. We have recently found evidence indicating the neuropilins form complexes with another VEGF receptor, VEGFR-1. However, the biological function of this complex remains to be elucidated.
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PMID:The VEGF splice variants: properties, receptors, and usage for the treatment of ischemic diseases. 1082 52

The formation of new blood vessels (angiogenesis) is essential for embryonic development and contributes to the pathogenesis of numerous disorders. In contrast, insufficient angiogenesis may lead to tissue ischemia and failure. The recent discovery of novel angiogenic molecules has initiated efforts to improve tissue perfusion via therapeutic angiogenesis. However, rational design of such treatment strategies mandates a better understanding of the molecular mechanisms of angiogenesis. In this brief review, the role of a prime angiogenic candidate, namely vascular endothelial growth factor (VEGF) and its homologues, in physiological and pathological angiogenesis will be discussed with particular attention to myocardial ischemia and heart failure. In addition, a novel interaction between the junctional protein vascular endothelial-cadherin (VE-cadherin) and VEGF, essential for the endothelial survival function of VEGF, will be reviewed.
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PMID:Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. 1086 45

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have both shown strong angiogenetic effects in ischemic animal models and it has been reported that these growth factors were increased after acute myocardial ischemia. However, there have been few reports on the serum levels of bFGF and VEGF after acute myocardial infarction (AMI), in particular there has not been a comparative study of bFGF and VEGF in human subjects. The time course of circulating levels of bFGF and VEGF was examined in 36 patients with AMI who were within 24h of the onset of the AMI. The serum bFGF and VEGF levels of 50 age- and sex-matched healthy volunteers served as the baseline value. All the patients had undergone coronary angiography on the day of admission (Day 0), but prior to that the serum bFGF and VEGF levels were examined by enzyme-linked immunoassay. The serum bFGF and VEGF levels were also evaluated on Days 7, 14 and 28. Creatine kinase, myosin light chain I and troponin-T were measured subsequently and radionuclide examinations were performed during the early phase of AMI to determine the infarct size. The serum bFGF levels were significantly increased at Day 0 and were maintained until Days 7 and 14. Although serum VEGF levels at Day 0 were similar to the baseline values, they showed a remarkable increase by Days 7 and 14. A high serum level of bFGF was detected in the acute phase of AMI, and a later increase in VEGF was determined in the sub-acute phase, which suggest that these 2 growth factors play an important role at different time points of the reconstructing process of infarcted myocardial tissue.
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PMID:Elevated circulating levels of basic fibroblast growth factor and vascular endothelial growth factor in patients with acute myocardial infarction. 1094 14

The formation of new blood vessel is essential for a variety of physiological processes like embryogenesis and the female reproduction as well as wound healing and neovascularization of ischemic tissue. Major progress in understanding the underlying mechanisms regulating blood vessel growth has offered novel therapeutic options in the treatment of a variety of diseases including ischemic cardiovascular disorders. Vasculogenesis and angiogenesis are the mechanisms responsible for the development of the blood vessels. Angiogenesis refers to the formation of capillaries from preexisting vessels in the embryo and adult organism. While pathologic angiogenesis includes the role of post-natal neovascularization in the pathogenesis of arthritis, diabetic retinopathy, and tumor growth and metastasis, therapeutic angiogenesis, either endogenously or in response to administered growth factors, includes the development of collateral blood vessels in tissue ischemia. Preclinical studies established that angiogenic growth factors could promote collateral artery development in animal models of peripheral and myocardial ischemia. Subsequent clinical trials using gene transfer of naked DNA encoding for VEGF for the treatment of critical limb and myocardial ischemia documented the safety and clinical benefit of this novel therapeutic approach. Several objective methods indicated marked improvement in collateral vessel development. Vasculogenesis describes the development of new blood vessels from in situ differentiating endothelial cells. Recently considered to be restricted to embryogenesis, there exists now striking evidence that endothelial progenitor cells (EPC) circulate also in adult peripheral blood able to participate in ongoing neovascularization. Different cytokines and growth factors have a stimulatory effect on these bone-marrow derived EPC. Granulocyte macrophage colony stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) mobilize EPC from the bone marrow into the peripheral circulation. While their endogenous contribution to postnatal neovascularization needs to be documented, the iatrogenic expansion and mobilization of EPC might represent an effective means to augment the resident population of endothelial cells (ECs). This kind of cell therapy for tissue regeneration in ischemic cardiovascular diseases opens a novel and challenging clinical option besides or in addition to the use of growth factors in gene therapy.
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PMID:[Angiogenesis and vasculogenesis. Therapeutic strategies for stimulation of postnatal neovascularization]. 1107 19

The central role of vascular endothelial growth factor (VEGF) in angiogenesis in health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs and as a pro-angiogenic cytokine for the treatment of ischaemic heart disease. While VEGF binds to two receptor protein tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (KDR), most biological functions of VEGF are mediated via VEGFR2, and the role of VEGFR1 is currently unknown. Neuropilin-1, a non-tyrosine kinase transmembrane molecule, may function as a co-receptor for VEGFR2. Considerable progress has recently been made towards delineating the signal transduction pathways distal to activation of VEGFR2. Activation of the mitogen-activated protein kinase, protein kinase C and Akt pathways are all strongly implicated in mediating diverse cellular biological functions of VEGF, including cell survival, proliferation, the generation of nitric oxide and prostacyclin and angiogenesis. Upregulation of metalloproteinases, activation of focal adhesion kinase and interactions between VEGF receptors and integrins are strongly implicated in VEGF-induced endothelial cell migration. Recent findings suggest important roles for the vasodilators nitric oxide and prostacyclin, in linking post-receptor signaling networks to downstream biological effects and in mediating some in vivo endothelial functions of VEGF.
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PMID:Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. 1116 70

Myocardial ischaemia affects left ventricular relaxation. The velocity of propagation of rapid left ventricular filling flow (VPF, cm/s) measured by colour M-mode is strongly correlated with the haemodynamic constant of left ventricular relaxation (Tau). The authors compared the changes in VPF during stress echocardiography with Dobutamine in a control group of non-coronary patients (Group 1, N = 12) and a group of coronary patients (Group 2, N = 29). Coronary angiography was performed in all patients. The basal VPF were similar in both groups (Group 1: 68.3 +/- 22.7 cm/s vs Group 2: 66.2 +/- 23.1 cm/s, NS). The VPF at the peak of dobutamine infusion were significantly different from the values observed under basal conditions in Group 1 (105.1 +/- 25.0 cm/s, p < 0.001) whereas this difference was not significant in Group 2 (67.4 +/- 19.3 cm/s, NS). There were significant differences between the two groups for peak values (p < 0.001) and for percentage variation of VPF (peak-basal value/basal value) with respect to the basal values (Group 1: 63 +/- 43% vs Group 2: 9 +/- 39%, p < 0.01). A percentage variation of VPF < 25% (Group 1: 3/12 patients and Group 2: 23/29 patients) allows detection of coronary artery disease with a sensitivity of 79% and a specificity of 75%. During Dobutamine infusion, the velocity of propagation of left ventricular filling flow increases less in coronary patients than in non-coronary patients. The study of this quantitative parameter of left ventricular relaxation seems to be a valuable tool for detecting the presence of coronary artery disease during stress echocardiography.
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PMID:[Changes in velocity of left ventricular filling measured by color M-mode during dobutamine stress echocardiography]. 1122 20

Acidic fibroblast growth factor (FGF) is a potent mitogen that can induce angiogenesis in vivo. We have recently reported a marked increase of basic FGF in the pericardial fluid of patients with severe coronary stenosis and an increase in vascular endothelial growth factor (VEGF) in the pericardial fluid of patients with severe myocardial ischemia. The purpose of this study was to evaluate whether acidic FGF levels in the pericardial fluid are associated with severe myocardial ischemia. Immediately after incision of the pericardium in 48 patients during open-heart surgery, 3-5ml of pericardial fluid was obtained. Concentrations of basic FGF and VEGF in the pericardial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). The ELISA system for human acidic FGF was newly developed using a rabbit antibovine acidic FGF antibody. The patients were divided into three groups (group A: 13 patients undergoing emergency coronary artery bypass grafting (CABG) for unstable angina; group B: 17 patients undergoing elective CABG for stable angina; group C: 18 patients undergoing nonischemic open-heart surgery). The VEGF level in the pericardial fluid in group A was 68 +/- 59pg/ml, which was significantly higher than 33 +/- 9 pg/ml in group B and 31 +/- 20 pg/ml in group C (P < 0.05). The concentrations of basic FGF in the pericardial fluid in groups A and B were 722 +/- 601 and 773 +/- 763pg/ml, respectively, significantly higher than 263 +/- 349pg/ml in group C. The pericardial acidic FGF level in group A was 4,291 +/- 2,336 pg/ml, which was also significantly higher than 2,386 +/- 1,048 pg/ml in group B and 2,589 +/- 990 pg/ml in group C (P < 0.05). The acidic FGF level correlated well with the level of VEGF (r = 0.61, P < 0.0001). It is concluded that the level of acidic FGF in pericardial fluid is associated with severe myocardial ischemia. This result indicates that the release of acidic FGF from the myocardial tissue into pericardial fluid is closely related to severe myocardial ischemia.
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PMID:Myocardial ischemia enhances the expression of acidic fibroblast growth factor in human pericardial fluid. 1128 98

Ischemic preconditioning (IP) exerts cardioprotection through protein kinase C (PKC) activation, whereas myocardial ischemia enhances vascular endothelial growth factor (VEGF) mRNA expression. However, the IP effect or the involvement of PKC on the VEGF expression is unknown in myocardial infarction. We investigated whether IP enhances VEGF gene expression and angiogenesis through PKC activation in the in vivo myocardial infarction model. Sprague-Dawley rats were assigned into the following 3 groups: the sham group; the IP group, which underwent 3 cycles of 3 minutes of ischemia and 5 minutes of reperfusion (IP procedure); and the non-IP group. The latter 2 groups were subsequently subjected to left anterior descending coronary artery occlusion. To examine the involvement of PKC, the PKC inhibitor chelerythrine (5 mg/kg) or bisindolylmaleimide (1 mg/kg) was injected intravenously before the IP procedures. PKCepsilon was translocated to the nucleus after 10 minutes of ischemia after the IP procedure but was not translocated in the non-IP and the sham groups. VEGF mRNA expression 3 hours after infarction was significantly higher in the IP group than in the non-IP and the sham groups. Capillary density in the infarction was significantly higher, whereas the infarct size was smaller in the IP group than in the non-IP group at 3 days of infarction. Chelerythrine but not bisindolylmaleimide blocked all of the IP effects on the nuclear translocation of PKCepsilon, enhancement of VEGF mRNA expression and angiogenesis, and infarct size limitation. These results show that IP may enhance VEGF gene expression and angiogenesis through nuclear translocation of PKCepsilon in the infarcted myocardium.
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PMID:Ischemic preconditioning upregulates vascular endothelial growth factor mRNA expression and neovascularization via nuclear translocation of protein kinase C epsilon in the rat ischemic myocardium. 1130 92


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