Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus vectors are capable of high efficiency in vivo arterial gene transfer, and are currently in use as therapeutic agents in animal models of vascular disease. However, despite substantial data on the ability of viruses to cause vascular inflammation and proliferation, and the presence in current adenovirus vectors of viral open reading frames that are translated in vivo, no study has examined the effect of adenovirus vectors alone on the arterial phenotype. In a rabbit model of gene transfer into a normal artery, we examined potential vascular cell activation, inflammation, and neointimal proliferation resulting from exposure to replication-defective adenovirus. Exposure of normal arteries to adenovirus vectors resulted in: (a) pronounced infiltration of T cells throughout the artery wall; (b) upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in arterial smooth muscle cells; (c) neointimal hyperplasia. These findings were present both 10 and 30 d after gene transfer, with no evidence of a decline in severity over time. Adenovirus vectors have pleiotropic effects on the arterial wall and cause significant pathology. Interpretation of experimental protocols that use adenovirus vectors to address either biological or therapeutic issues should take these observations into account. These observations should also prompt the design of more inert gene transfer vectors.
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PMID:Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. 867 67

Proteins or lipids exposed to aldose sugars undergo initial and ultimately irreversible modification resulting in the formation of so-called advanced glycation end-products (AGEs). AGEs are postulated to be especially important in the setting of diabetes mellitus due to hyperglycaemia characteristic of this disorder. Our work has demonstrated that one of the principal means by which AGEs interact with the vascular wall is by interaction with their cellular receptor, the receptor for advanced glycation end-products (RAGE), which is present on the surface of endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. AGEs interact with RAGE, resulting in the induction of monocyte chemotaxis as well as oxidant stress. One of the consequences of AGE-RAGE-induced cellular oxidant stress is the enhanced expression of vascular cell adhesion molecule-1 on the endothelial surface, a critical consequence of which is the attraction of mononuclear phagocytes into the vessel wall. In both cases, the pro-inflammatory effects of AGEs may be inhibited in the presence of RAGE blockade, using either anti-RAGE F(ab')2 or soluble RAGE, the extracellular domain of the molecule. These data suggest that inhibition of RAGE may interfere with monocyte chemotaxis and attraction into the vessel wall where AGEs deposit/form, suggesting the potential of this intervention to interfere with a critical step in the development of vascular disease, especially in patients with diabetes.
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PMID:The receptor for advanced glycation end-products has a central role in mediating the effects of advanced glycation end-products on the development of vascular disease in diabetes mellitus. 904

We have recently shown that ex vivo gene therapy of rabbit autologous vein grafts with antisense oligodeoxynucleotides (AS ODN) blocking cell cycle regulatory gene expression inhibits not only neointimal hyperplasia, but also diet-induced, accelerated graft atherosclerosis. We observed that these grafts remained free of macrophage invasion and foam cell deposition. Since endothelial dysfunction plays an important role in vascular disease, the current study examined the effect of this genetic engineering strategy on graft endothelial function and its potential relationship to the engineered vessels' resistance to atherosclerosis. Rabbit vein grafts transfected with AS ODN against proliferating cell nuclear antigen (PCNA) and cell division cycle 2 (cdc2) kinase elaborated significantly more nitric oxide and exhibited greater vasorelaxation to both calcium ionophore and acetylcholine than did untreated or control ODN-treated grafts. This preservation of endothelial function was associated with a reduction in superoxide radical generation, vascular cell adhesion molecule-1 (VCAM-1) expression, and monocyte binding activity in grafts in both normal and hypercholesterolemic rabbits. Our data demonstrate that AS ODN arrest of vascular cell cycle progression results in the preservation of normal endothelial phenotype and function, thereby influencing the biology of the vessel wall towards a reduction of its susceptibility to occlusive disease.
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PMID:Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts. 907 39

Secondary prevention of atherosclerosis, especially before the onset of symptoms, appears desirable and could be possible with a serum marker detecting atherosclerosis. Circulating, shedded forms of adhesion molecules may serve as such because their expression is upregulated in atherosclerotic plaques. In 52 patients with peripheral arterial vascular disease (Fontaine class IIa, 7 patients; class IIb, 29 patients; and class III, 16 patients), the extent of atherosclerosis was evaluated on the basis of angiograms of a large portion of the arterial system. The area diseased by atherosclerosis was determined by the percentage of vessel wall irregularities of the following calculated segments: aorta (distal from the kidney arteries), common iliac artery, external iliac artery, common femoral artery, lateral circumflex femoral artery, and popliteal artery. The maximal surface area that could exhibit atherosclerotic changes was 250 cm2. The serum concentration of circulating vascular cell adhesion molecule-1 (VCAM-1) correlated with the extent of atherosclerosis (r = .8, P < .001). In contrast, circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin (as markers for endothelial cell damage) did not correlate with the extent of atherosclerosis. Furthermore, circulating VCAM-1 could be used to indicate stages of atherosclerosis with a high degree of statistical significance. The potential bias of factors such as age, diabetes mellitus, hypercholesterolemia, arterial hypertension, renal failure, and history of myocardial infarction on the correlation of circulating VCAM-1 with the extent of atherosclerosis could be excluded by multivariate analysis. These findings suggest an important role of VCAM-1 in atherosclerosis and may serve as the basis for further evaluation of circulating VCAM-1 as a potential serum marker for atherosclerosis.
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PMID:Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. 910 69

The NF-kappa B transcription factor family and its inhibitory proteins (I kappa B) form an autoregulatory system that has been linked to endothelial gene expression and vascular disease. To determine the role of the NF-kappa B/I kappa B system in smooth muscle cells (SMCs) in vivo, the present study used the balloon catheter injury model in the rat carotid artery. The NF-kappa B family members p50, p65, p52, c-Rel, and RelB as well as the inhibitor proteins I kappa B alpha, I kappa B beta, and p105 were present in uninjured arteries as determined by immunoblotting. Using electromobility shift assays, low levels of constitutively activated p50, p65, and c-Rel were seen in normal carotid arteries and a fivefold induction occurred during times of rapid SMC proliferation and neointima formation after balloon denudation. Furthermore, immediately after injury, the levels of I kappa B alpha, I kappa B beta, and p105 were dramatically reduced. Expression of the NF-kappa B-regulated genes, vascular cell adhesion molecule (VCAM)-1 and monocyte chemotactic protein (MCP)-1, was apparent in SMCs within 4 hours after injury. Macrophage infiltration occurred in parallel with the expression of VCAM-1 and MCP-1, and these inflammatory cells were present on the luminal surface of injured vessels during intimal lesion formation. In chronically denuded vessels, the SMCs on the luminal surface continued to express high levels of VCAM-1 and MCP-1, which may account for the increased presence of macrophages. Together, these findings link the activation of NF-kappa B to intimal lesion formation and to the inflammatory response associated with SMCs after vascular injury.
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PMID:Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. 932 42

To investigate the metabolic and genetic associations of levels of soluble adhesion molecules, plasma levels of soluble E-selectin and vascular cell adhesion molecule-1 were measured in 60 non-insulin-dependent diabetes mellitus (NIDDM) patients, 60 first-degree relatives of NIDDM patients and 60 control subjects, none of whom displayed clinical features of vascular disease. In addition, E-selectin A561C genotype, coding for a serine to arginine change, was determined. E-selectin levels were elevated in the patient group; 57 [52-63] (mean [95% confidence intervals]) ng/ml, compared with both relatives; 44 [39-50] ng/ml p = 0.001 and controls 39.5 [36-43] ng/ml p = 0.0001. E-selectin levels correlated with triglycerides, tissue-plasminogen activator and plasminogen activator inhibitor-1 activity in all groups. Levels of E-selectin were related to E-selectin genotype, being higher in subjects possessing the arginine allele (51.4 vs 44.5 ng/ml p < 0.05). E-selectin levels were higher in males than females in controls (female 35 [32-39] vs male 45 [40-51] ng/ml p = 0.004), and NIDDM relatives (female 38 [33-44] vs male 52 [45-61] ng/ml p = 0.004) but not in NIDDM patients where levels were similar (female 58 [49-69] vs male 56 [50-62] ng/ml, ns). There was no difference in soluble vascular cell adhesion molecule-1 levels between the three groups (control 640 [598-686] ng/ml, NIDDM relatives 634 [593-678] ng/ml and NIDDM patients 664 [608-725] ng/ml). In controls and patients vascular cell adhesion molecule-1 levels correlated with von Willebrand factor (vWF). The results indicate that levels of E-selectin relate to vascular risk factors in control subjects, NIDDM relatives and NIDDM patients.
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PMID:Soluble vascular cell adhesion molecule-1 and E-selectin levels in relation to vascular risk factors and to E-selectin genotype in the first degree relatives of NIDDM patients and in NIDDM patients. 956 51

Activation of endothelial cells and dedifferentiation of smooth muscle cells (SMC) are events in the development of vascular disease. The NF-kappaB transcription factor family and its inhibitory proteins (IkappaB) have been implicated in regulating the expression of genes associated with the concomitant inflammatory response. To determine the role of the NF-kappaB/IkappaB system in vivo, the present study used the balloon catheter injury model in the rat carotid artery. Immunoblotting revealed that higher levels of the NF-kappaB family members p50, p52, p65, c-Rel, and RelB were expressed in injured arteries during lesion formation compared to normal vessels. Using electromobility shift assays, low levels of constitutively activated NF-kappaB were seen in normal carotid arteries and an induction occurred during times of rapid SMC proliferation. Furthermore, immediately after injury, the levels of the inhibitor proteins IkappaB alpha, IkappaB beta, and p105 were dramatically reduced. Consistent with the activation of NF-kappaB, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) were induced in SMC and endothelial cells as early as 4 h after injury and this was accompanied by adhesion of monocytes/macrophages. SMC forming a pseudoendothelium in chronically denuded vessels continued to express high levels of VCAM-1 and MCP-1, thus perpetuating the inflammatory response. These findings link the activation of NF-kappaB to the inflammatory response and to intimal lesion formation following vascular injury.
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PMID:The NF-kappaB and IkappaB system in injured arteries. 976 79

The transcriptional nuclear factor (NF)-kappaB can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis. Because oxidative stress may play a key role in the pathogenesis of diabetic vascular disease, we have examined whether culture of porcine vascular smooth muscle cells (PVSMCs) under high glucose (HG) conditions (25 mmol/l) to simulate the diabetic state can lead to the activation of NF-kappaB, and also whether cytokine- or growth factor-induced NF-kappaB activation is altered by HG culture. We observed that PVSMCs cultured in HG showed significantly greater activation of NF-kappaB in the basal state compared with cells cultured in normal glucose (NG) (5.5 mmol/l). Treatment of the cells with cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1beta, or with growth factors, such as platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor, all led to NF-kappaB activation in cells cultured in both NG and HG. However, their effects were markedly greater in HG. The augmented TNF-alpha-induced NF-kappaB activation in HG was associated with increased TNF-alpha-mediated transcriptional activation of the vascular cell adhesion molecule-1 promoter. Immunoblotting with an antibody to the p65 subunit of NF-kappaB indicated that the levels of this protein were higher in the nuclear extracts from cells cultured in HG compared with NG. Cells cultured in HG also produced significantly greater amounts of the reactive oxygen species superoxide. HG-induced NF-kappaB activation was inhibited by a protein kinase C inhibitor, calphostin C. These results suggest that hyperglycemia-induced activation of NF-kappaB in VSMCs may be a key mechanism for the accelerated vascular disease observed in diabetes.
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PMID:Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. 1010 4

Diabetes mellitus is complicated with vascular disorders such as atherosclerosis (macroangiopathy) and retinopathy (microangiopathy). In macroangiopathy, AGE plays an important role in atherogesis through NF-kappa B activation, that induces VCAM-1 and MCP-1. Diabetic retinopathy is based on the microangiopathy characteristic of angiogenesis. VEGF is a key substance in the angiogenesis in the retina. VEGF is produced from retinal cells exposed to AGE, adenosine, bFGF. VEGF elictes angiogenesis and increased vascular permeability (retinal edema). I consider that AGE is the most important substance in diabetic vascular disorder. Therefore, I expect a new application for diabetic angiopathy to suppress the effect of AGE.
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PMID:[Vascular endothelial cell dysfunction in diabetes mellitus]. 1019 36

Atherosclerosis, the main cause of ischemic heart disease, is a process with relevant inflammatory components, in which LDL-cholesterol, largely emphasized in the last years as a "causal" factor following the improvement in prognosis with cholesterol-lowering agents, is only one of the culprits. Despite the use of new cholesterol-lowering drugs, atherosclerotic vascular disease will likely continue to be the main cause of death in Western countries. Furthermore, the statistical relationship between cholesterol and cardiovascular mortality only explains a relatively minor component of differences in mortality among diverse countries. For these reasons, the interest in preventive approaches complementary or alternative to cholesterol reduction should be one of the main objectives of cardiovascular research in the years to come. Already in the '70s the very low incidence of atherosclerotic diseases in Mediterranean countries (Greece and Southern Italy) and the importance of the "dietary factor" in such protection were noticed. Diets for people in these countries are, among other components, very rich in oleic acid, the main constituent of olive oil, with about 29% of daily caloric intake derived from monounsaturated fatty acids. Oleic acid, besides exerting relatively minor effects on the quantitative and qualitative regulation of cholesterol levels, appears to interfere directly with the inflammatory response that characterizes early atherogenesis. The endothelial expression of adhesion molecules for circulating monocytes, induced by inflammatory cytokines, minimally oxidized LDL and the advanced glycation end-products present in diabetes, substantially contributes to the onset and early progression of atherosclerosis. In an in vitro model of early atherogenesis based on cultured endothelial cells stimulated by cytokines, we observed that the incorporation of oleic acid in total cell lipids--mostly at the expenses of saturated fatty acids--decreases the expression of several endothelial leukocyte adhesion molecules, among which vascular cell adhesion molecule-1, involved in the selective monocyte recruitment in the arterial intima. Oleic acid also determines a parallel reduction in messenger RNA for this molecule, interfering with the activation of the most important transcription factor controlling endothelial activation, nuclear factor-kappa B. Thus, possibly in concert with other more highly unsaturated fatty acids, oleic acid may contribute to the prevention of atherosclerosis also through a modulation of gene expression for endothelial leukocyte adhesion molecules. This series of investigations emphasizes the possibility of preventive interventions in atherosclerosis based on the modulation of vascular response to classical "triggers" (cholesterol, advanced glycation end-products of diabetes), an intervention strategy fundamentally different from--and thereby complementary to--those now more in fashion.
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PMID:Direct vascular antiatherogenic effects of oleic acid: a clue to the cardioprotective effects of the Mediterranean diet. 1044 51


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