Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenic therapy using fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) is being developed as a novel therapeutic strategy to obtain restoration of blood flow around the ischemia in cases of ischemic cardiovascular disease. In addition, arterial gene therapy through gene transfer by VEGF genes has now reached the stage of clinical application. Through in vivo animal experiments to determine the angiogenic effects of FGF and VEGF, we hope to obtain clues concerning the clinical applications of these methods. Methods-1: Twenty-three adult dogs were divided into 3 groups as follows: Group A-1: 20 micrograms of bFGF was administered intravenously simultaneously with heparin three times per week in 4 dogs. Group A-2: 20 micrograms of bFGF was administered intravenously three times a week without heparin in 4 dogs. Group B: 20 micrograms of bFGF was administered intramuscularly three times per week in 5 dogs. Group C: Sham operation control group consisting of 10 dogs. Local ischemia was created in the hind limbs of animals in groups A-1, A-2 and B through ligation of the femoral artery. Selective femoral arteriography was performed immediately after ligation at 1 week and 2 weeks postoperatively. Biopsy was also performed either at 1 week or 2 weeks after ligation. Results-1: (1) The percent increase in number of collateral vessels of the ischemic zone, as recognized on arteriography, was greater in the bFGF groups compared to group C. (2) The increase in collateral vessels peaked at 1 week. (3) No difference in angiogenic effect was observed in relation to the method of administration. (4) The combined administration of heparin had no angiogenic effect. (5) The hemoglobin content of the biopsy specimens was significantly greater in the 3 groups receiving bFGF compared to group C. Methods-2: The same study was performed using VEGF as detailed in Method-1. Results-2: As in the first experiment, a significant increase in collateral vessels was seen in the VEGF group compared to the control group. Both exogenous bFGF and VEGF significantly promote collateral vessel development and appear to be effective novel therapeutic agents for the treatment of ischemic disease.
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PMID:Angiogenesis. Angiogenic therapy using fibroblast growth factors and vascular endothelial growth factors for ischemic vascular lesions. 877 22

Angiogenic cytokines constitute a potentially novel form of therapy for patients with cardiovascular disease. The feasibility of using recombinant formulations of angiogenic growth factors to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia, "therapeutic angiogenesis", has now been well established. These studies have suggested that two angiogenic growth factors in particular, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are sufficiently potent to merit further investigation. More recently, experiments performed in our laboratory have indicated that in the case of VEGF, a secreted protein, similar results may be achieved by percutaneous arterial gene transfer. Further laboratory and clinical studies may yield promising insights into the fundamental basis for native as well as therapeutic angiogenesis and at the same time more explicitly define the manner in which therapeutic angiogenesis may be successfully incorporated into clinical practice.
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PMID:The role of angiogenic cytokines in cardiovascular disease. 881 Oct 67

The feasibility of a single administration of a replication-deficient adenovirus (Ad) vector encoding the cDNA for human vascular endothelial growth factor (VEGF) (AdCMV.VEGF) to induce neovascularization in vivo in normal tissue was evaluated in retroperitoneal adipose tissue. Following administration of AdCMV.VEGF (10(9) pfu/50 microliters), maximal VEGF cDNA expression was observed at 2-5 days in the injected adipose tissue. No VEGF protein was detected at > or = 10 days in injected adipose tissue, and there was no increase in serum VEGF levels at any time. In vivo quantification of the number of blood vessels using 30x visualization of the adipose tissue demonstrated an increase in vessel number by 10 days, plateauing by 30 days with a 123% increase in vessel number compared to the control vector AdCMV.Null, despite the fact that no VEGF protein was detected after 5 days. Consistent with the in vivo data, histologic quantification of capillary number demonstrated an increase by day 5, reaching a 38% increase over AdCMV.Null by day 30. These observations demonstrate that an Ad vector carrying the VEGF cDNA is capable of inducing the growth of new blood vessels in a regional fashion in a relatively avascular, normal organ. This suggests in vivo Ad-mediated gene transfer may be useful for therapeutic angiogenesis in the treatment of ischemic cardiovascular disease.
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PMID:Regional angiogenesis induced in nonischemic tissue by an adenoviral vector expressing vascular endothelial growth factor. 901 25

Cardiovascular disease and cancer account for the majority of adult disease in the developed world. This review focuses on current concepts in the study of angiogenesis (new vessel formation) as related to these conditions and highlights the role of vascular endothelial growth factor. Developments in therapeutic angiogenesis have raised the possibility that pharmacologic or gene-directed interventions, based on the ability of vascular endothelial growth factor to promote new vessel formation, may soon gain clinical application for the treatment of occlusive vascular disease. Similarly, the future treatment of malignant disease is likely to involve antiangiogenic agents that, in preliminary animal work, have demonstrated an efficacy that is not limited by adverse affects. Aside from these potential applications, current investigations have enhanced our understanding of mechanisms involved in the development of atherosclerotic and malignant disease.
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PMID:Angiogenesis in the pathobiology and treatment of vascular and malignant diseases. 935 65

Blood vessels affect the quality of life in many ways. They provide an essential nutritive function during growth and repair of tissues but, on the other hand, can become affected by disorders or trauma, resulting in bleeding, thrombosis, arterial stenosis, and atherosclerosis. Three molecular systems, the vascular endothelial growth factor (VEGF) system, the plasminogen system, and the coagulation system, have been implicated in the formation and pathobiology of blood vessels. This review focuses on the role of these systems in these processes. Recent gene-targeting studies have identified VEGF as a potent modulator of the formation of endothelial cell-lined channels. Somewhat unanticipated, the initiator of coagulation is not only involved in the control of hemostasis but also in the maturation of a muscular wall around the endothelium. With different murine models of cardiovascular disease, a pleiotropic role of the plasminogen system was elucidated in thrombosis, in arterial neointima formation after vascular wound healing and allograft transplantation, in atherosclerosis, and in the formation of atherosclerotic aneurysms. Surprisingly, tissue-type plasminogen activator is also involved in brain damage after ischemic or neurotoxic insults. The insights from these gene-targeting studies have formed the basis for designing gene therapy strategies for restenosis and thrombosis, which have been successfully tested in these knockout models.
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PMID:Molecular analysis of blood vessel formation and disease. 937 41

Angiogenic cytokines constitute a potentially novel form of therapy for patients with cardiovascular disease. The feasibility of using recombinant formulations of angiogenic growth factors to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia--'therapeutic angiogenesis'--has now been well established. These studies have suggested that two angiogenic growth factors in particular--basic fibroblast growth factor and vascular endothelial growth factor--are sufficiently potent to merit further investigation. More recently, experiments performed in our laboratory have indicated that, in the case of vascular endothelial growth factor--a secreted protein--similar results may be achieved by percutaneous arterial gene transfer. Further laboratory and clinical studies may yield promising insights into the fundamental basis for native as well as therapeutic angiogenesis, and at the same time more explicitly define the manner in which therapeutic angiogenesis may be successfully incorporated into clinical practice.
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PMID:Therapeutic angiogenesis: a new frontier for vascular therapy. 954 20

Correlative studies have indicated that hyperinsulinemia is present in many individuals with atherosclerosis. Insulin resistance has also been linked to cardiovascular disease. It has proved to be difficult to decipher whether hyperinsulinemia or insulin resistance plays the most important role in the pathogenesis of atherosclerosis and coronary artery disease. In this study, we demonstrate that insulin increases the amount of farnesylated p21Ras in vascular smooth muscle cells (VSMC), thereby augmenting the pool of cellular Ras available for activation by platelet-derived growth factor (PDGF). In VSMC incubated with insulin for 24 h, PDGF's influence on GTP-loading of Ras was significantly increased. Furthermore, in cells preincubated with insulin, PDGF increased thymidine incorporation by 96% as compared with a 44% increase in control cells (a 2-fold increment). Similarly, preincubation of VSMC with insulin increased the ability of PDGF to stimulate gene expression of vascular endothelial growth factor 5- to 8-fold. The potentiating influence of insulin on PDGF action was abrogated in the presence of a farnesyltransferase inhibitor. Thus, the detrimental influence of hyperinsulinemia on the arterial wall may be related to the ability of insulin to augment farnesyltransferase activity and provide greater amounts of farnesylated p21Ras for stimulation by various growth promoting agents.
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PMID:Insulin potentiates platelet-derived growth factor action in vascular smooth muscle cells. 975 84

The increase in vascular wall stress imposed by hypertension has been strongly implicated in the pathogenesis of cardiovascular disease. Much of this chronic cyclical mechanical strain is experienced by the vascular smooth (VSM) cells of the vascular media. The cellular mechanisms whereby VSM cells sense and respond to changing mechanical forces are poorly understood. This review focuses on an emerging field of cardiovascular research in which the direct effects of mechanical strain on VSM cells and isolated blood vessels in organ culture have been characterized, in vitro. Cyclical mechanical strain profoundly influences cultured VSM cell orientation, growth and phenotype. Mechanical strain also increases the secretory function of VSM cells leading to increased extracellular matrix protein production. Vasoactive mediators such as angiotensin II potentiate these effects. Mechanical strain increases VSM cell release of platelet derived growth factor, transforming growth factor beta1, fibroblast growth factor and vascular endothelial growth factor, which act in autocrine or paracrine loops to influence VSM and endothelial cell growth and function. Mechanical strain may also activate local tissue renin-angiotensin systems and regulate expression of angiotensin II receptors within the cardiovascular system. The mechanism whereby VSM cells transduce mechanical stimuli into an intracellular signal and biological response, i.e. 'mechanotransduction', is strongly dependent on integrins. Moreover, specific matrix protein:integrin engagements lead to differential VSM cells responses via the selective activation of numerous intracellular signalling pathways including; mitogen-activated protein kinase, focal adhesion kinase and c-Src. The study of vascular mechanotransduction has begun to delineate the complex cellular basis of cardiovascular structural and functional modification in hypertension.
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PMID:Mechanical influences on vascular smooth muscle cell function. 988 78

Hypoxia is an essential pathophysiologic component of ischemic cardiovascular disease. A better understanding of the molecular mechanisms underlying adaptive responses to hypoxia may lead to novel therapeutic strategies. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS domain transcription factor that mediates changes in gene expression in response to changes in O2 concentration. Genes that are transcriptionally activated by HIF-1 in hypoxic cells encode proteins that increase O2 delivery or allow metabolic adaptation to limited O2 availability. HIF-1 target genes include those encoding vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters, and glycolytic enzymes. In anemic fetal sheep, increased myocardial vascularization was associated with concomitant increases in the expression of HIF-1 and VEGF. Expression of HIF-1 target genes was not induced by hypoxia in embryonic stem cells lacking expression of the O2-regulated HIF-1 alpha subunit. Mouse embryos lacking HIF-1 alpha expression arrested in their development by E9.0 and died by E10.5 with cardiovascular malformations and massive cell death throughout the embryo. These studies indicate that HIF-1 functions as a master regulator of O2 homeostasis that controls the establishment of essential physiologic systems during embryogenesis as well as their subsequent utilization during fetal and postnatal life.
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PMID:Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1. 1041 37

Cardiovascular diseases are the most important cause of death and hospitalisation in industrialised countries. Although pharmacological, interventional and surgical therapy has achieved major progress during the past 25 years, most therapeutic measures are only transiently effective or require life-long medication. Molecular cardiology aims at applying molecular biological methods for both diagnosis and treatment of cardiovascular disease. With respect to diagnosis of cardiac diseases such as hypertrophic cardiomyopathy or the long QT syndrome, it has become possible to characterise mutations in the genome responsible for the disease process. It is interesting that different mutations inducing hypertrophic cardiomyopathy are associated with a different prognosis and survival time. This example demonstrates that molecular biological analysis allows a better estimation of the individual risk in patients with a monogenetic disease. Such diseases are an important target for genetic therapies, as transfection of normal copies of the diseased gene would potentially cure the patient. Clinical experience has so far only been obtained in patients with familial hypercholesterolaemia and mutations in the LDL receptor. Molecular biology also permits a better understanding of the pathogenesis of atherosclerosis, which is responsible for most cardiovascular disease. Atherosclerosis is a disease of conduit arteries such as the aorta and the coronary arteries. In recent years it has become possible to characterise better the molecular and cellular changes leading to endothelial dysfunction, coronary vasospasm, adhesion of monocytes and lymphocytes, proliferation and migration of vascular smooth muscle cells, and formation of extracellular matrix. This improved understanding has led to new therapeutic approaches, although a genetic intervention is not probable for the moment due to the complexity of the disease process. Balloon dilatation of coronary arteries has generated a new disease, namely restenosis. Vascular remodelling and proliferation are of major importance for this disease. Many cellular mechanisms have been characterised, and gene therapeutic strategies including signal transduction and cell cycle regulation have already been investigated experimentally. Coronary bypass graft disease represents another target for gene therapy in the vascular system. Many experimental and a few clinical protocols have been performed with the saphenous vein. Yet another strategy for gene therapy is the endogenous formation of new vessels due to the effect of vascular endothelial growth factor. Molecular cardiology is a new and promising approach to a better understanding of cardiovascular disease. Genetic analysis is already established for the diagnosis of single gene disorders and, in addition, allows a more precise prognostic evaluation. Cardiovascular gene therapy has been focussing mainly on angiogenesis; other strategies, however, are under investigation mainly in an experimental setting.
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PMID:[Gene therapy in heart diseases]. 1060 53


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