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)

Obesity is more linked to vascular disease, including atherosclerosis and restenotic change, after balloon angioplasty. The precise mechanism linking obesity and vascular disease is still unclear. Previously we have demonstrated that the plasma levels of adiponectin, an adipose-derived hormone, decreases in obese subjects, and that hypoadiponectinemia is associated to ischemic heart disease. In current the study, we investigated the in vivo role of adiponectin on the neointimal thickening after artery injury using adiponectin-deficient mice and adiponectin-producing adenovirus. Adiponectin-deficient mice showed severe neointimal thickening and increased proliferation of vascular smooth muscle cells in mechanically injured arteries. Adenovirus-mediated supplement of adiponectin attenuated neointimal proliferation. In cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by growth factors including platelet-derived growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), basic fibroblast growth factor, and EGF and cell proliferation and migration induced by HB-EGF. In cultured endothelial cells, adiponectin attenuated HB-EGF expression stimulated by tumor necrosis factor alpha. The current study suggests an adipo-vascular axis, a direct link between fat and artery. A therapeutic strategy to increase plasma adiponectin should be useful in preventing vascular restenosis after angioplasty.
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PMID:Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. 1213 20

Humans have elevated serum uric acid as a result of a mutation in the urate oxidase (uricase) gene that occurred during the Miocene. We hypothesize that the mutation provided a survival advantage because of the ability of hyperuricemia to maintain blood pressure under low-salt dietary conditions, such as prevailed during that period. Mild hyperuricemia in rats acutely increases blood pressure by a renin-dependent mechanism that is most manifest under low-salt dietary conditions. Chronic hyperuricemia also causes salt sensitivity, in part by inducing preglomerular vascular disease. The vascular disease is mediated in part by uric acid-induced smooth muscle cell proliferation with activation of mitogen-activated protein kinases and stimulation of cyclooxygenase-2 and platelet-derived growth factor. Although it provided a survival advantage to early hominoids, hyperuricemia may have a major role in the current cardiovascular disease epidemic.
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PMID:Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. 1221 79

Foot ulcers secondary to peripheral neuropathy and vascular disease are a commonly occurring complication for people with diabetes. Becaplermin, a genetically-engineered growth factor in a hydrogel vehicle, has been shown to be more effective than vehicle-only control in healing chronic foot ulcers of patients with adequate vasculature receiving best clinical care. To evaluate the cost-effectiveness of adding up to 20 weeks of becaplermin to a regimen of best clinical care, a 1-year decision-analytic model was developed and tested using data from a previously published controlled clinical study involving 251 people with diabetes (124 becaplermin/127 control) and adequate vasculature presenting with an infection-free ulcer that had failed to heal despite appropriate therapy. A 20-week healing rate was estimated based on the clinical trial data assuming becaplermin treatment was terminated at 10 weeks in non-responding ulcers, and follow-up data were extended to 1 year. Resource utilization was estimated by an expert panel using a modified Delphi approach. Using the model, it was found that incorporating becaplermin with best clinical care resulted in 26 fewer ulcer-days per patient per year compared to best clinical care alone with an incremental cost-effectiveness ratio of $6 per ulcer-day averted. Results were sensitive to becaplermin cost, efficacy, and effect on infection and recurrence rates. The clinical benefits of becaplermin deserve further investigation to enhance cost-effectiveness information for informed treatment decisions.
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PMID:Cost-effectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers. 1465 15

Widely used tetracycline antibiotics affect many cellular functions relevant to human vascular disease including cell proliferation, migration, and matrix remodeling. We examined whether minocycline inhibited human aortic smooth muscle cell (HASMC) migration induced by vascular endothelial growth factor (VEGF). After the establishment of an optimal dose, minocycline treated HASMC were exposed to VEGF. HASMC migration, matrix metalloproteinase (MMP)-2 and MMP-9 activities, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) phosphorylation were determined by smooth muscle cell (SMC) invasion assay, real-time polymerase chain reaction, zymograms, and Western blot analysis, respectively. We demonstrated that VEGF and platelet-derived growth factor (PDGF)-induced SMC migration in a dose-dependent manner. MMP-9, but not MMP-2, mRNA was increased during VEGF stimulation. MMP-9 activity was increased from 1.5- to 2.5-fold in a dose-dependent manner (P<0.05). Both ERK1/2 and PI3K/AKt pathways were activated during VEGF-induced HASMCs migration. We then demonstrated that minocycline can inhibit VEGF-induced HASMC migration (P<0.05). The effects may be through the inhibition of MMP-9 mRNA transcription, protein activities and downregulation of ERK1/2 and PI3K/Akt pathway phosphorylation. Our results indicated that minocycline exerts multiple effects on VEGF-induced SMC migration, including inhibition of MMP-9 mRNA transcription and protein activities and downregulating ERK1/2 and PI3K signal pathways, suggesting minocycline may be a potentially therapeutic approach to inhibit disease process induced angiogenesis.
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PMID:Minocycline exerts multiple inhibitory effects on vascular endothelial growth factor-induced smooth muscle cell migration: the role of ERK1/2, PI3K, and matrix metalloproteinases. 1525 78

Diabetes mellitus is associated with an increased risk of vascular disease, with significant alterations in systemic endothelial progenitor cells (EPCs) and peripheral vascular function. To identify the contribution of the different vascular compartments in the diabetic impairment of vascularization, we employed streptozotocin- and control-treated 3-mo-old C57Bl/6 mice in an isogeneic pinnal cardiac allograft model, revealing a significant delay in vascularization of wild-type cardiac tissue transplanted into diabetic mice. To investigate the basis of this impairment, the function of diabetic bone marrow cells was tested by transplantation of bone marrow cells isolated from diabetic and control mice into intact, unirradiated 18-mo-old C57Bl/6 mice, which have impaired function of both EPCs and peripheral endothelial cells. Importantly, cells derived from control, but not diabetic, bone marrow integrated into transplanted cardiac allografts. To assess the contribution of diabetic changes in the local vasculature, diabetic mice were treated with pinnal injections of platelet-derived growth factor (PDGF)-AB, which promotes cardiac angiogenesis in wild-type mice. However, whereas PDGF-AB enhanced allograft function in control mice, the activity of the cardiac transplants in the PDGF-AB-treated diabetic mice was significantly decreased. To decipher the potential interactions between systemic bone marrow-derived cells and local vascular pathways, diabetic mice were transplanted with wild-type bone marrow cells with or without PDGF-AB pinnal pretreatment, resulting in improved allograft function and donor cell recruitment only in the combination treatment arm. Overall, these studies show that the diabetic impairment in cardiac angiogenesis can be reversed by targeting the synergism between local trophic pathways and systemic cell function.
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PMID:Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function. 1633 36

The development of blood vessels (angiogenesis) is critical throughout embryogenesis and in some normal postnatal physiological processes. Pathological angiogenesis has a pivotal role in sustaining tumour growth and chronic inflammation. Vascular endothelial growth factor-B (VEGF-B) is a member of the VEGF family of growth factors that regulate blood vessel and lymphatic angiogenesis. VEGF-B is closely related to VEGF-A and placenta growth factor (PlGF), but unlike VEGF-A, which binds to two receptor tyrosine kinases VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), VEGF-B and PlGF bind to VEGFR-1 and not VEGFR-2. There is growing evidence of a role for VEGF-B in physiological and pathological blood vessel angiogenesis. VEGF-B may provide novel therapeutic strategies for the treatment of vascular disease and be a potential therapeutic target in aberrant vessel formation. To help understand at the molecular level the differential receptor binding profile of the VEGF family of growth factors we have determined the crystal structure of human VEGF-B(10-108) at 2.48 Angstroms resolution. The overall structure is very similar to that of the previously determined cysteine-knot motif growth factors: VEGF-A, PlGF and platelet-derived growth factor-B (PDGF-B). We also present a predicted model for the association of VEGF-B with the second domain of its receptor, VEGFR-1. Based on this interaction and the present structural data of the native protein, we have identified several putative residues that could play an important role in receptor recognition and specificity.
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PMID:Crystal structure of human vascular endothelial growth factor-B: identification of amino acids important for receptor binding. 1661 87

In addition to combination treatment of pulmonary artery hypertension (PHT) with currently available drug options (endothelin-receptor inhibitors, phosphodiesterase-5 inhibitors, prostanoids). Numerous new drugs of other substance groups are being tested in preclinical and clinical studies. Most of the newly tried drugs use previously identified mechanisms of action that are involved in the development and progression of the underlying vascular disease. This has led to a certain paradigm shift which, in addition to vasodilatation and anti-platelet aggregation treatment, increasingly focuses on antiproliferative effects with the aim of preventing or regressing vascular remodelling. Of particular interest in this connection are tyrosine kinase inhibitors, which inhibit the action of such peptide growth factors as platelet-derived growth factor. Imatinib, one of this class of action, has given promising results in experimental studies and several case reports. Another greatly promising approach in the treatment of PHT are activators and simulators of soluble guanylyl cyclase, which are also currently being investigated in clinical trials.
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PMID:[Future aspects of the treatment of pulmonary arterial hypertension]. 1713 2

Calcium channel blockers (CCBs) have been shown to improve clinical outcomes in atherosclerotic vascular disease. The mechanisms underlying the vasculoprotective effects of a third-generation calcium channel blocker, azelnidipine, are incompletely understood. We asked whether azelnidipine attenuates atherosclerosis in monkeys and mice beyond its blood pressure-lowering effects. Cynomolgus monkeys were randomized to three groups after 4 weeks of a high cholesterol diet: control group (no treatment) and 3 and 10mg/kg daily azelnidipine; these doses have no effect on systemic arterial pressure or heart rate. Atherosclerosis was induced in the aorta by balloon injury, and the diet and treatment were continued for an additional 24 weeks. Azelnidipine did not affect blood lipid profiles, but reduced the development of atherosclerosis as detected by the elimination of local oxidative stress and reduced expression of monocyte chemoattractant protein-1 and platelet-derived growth factor. Azelnidipine also reduced the proliferation and migration of vascular smooth muscle cells in vitro. In atherosclerotic ApoE-knockout (ApoE-KO) mice fed a high cholesterol diet, azelnidipine but not amlodipine reduced the development of atherosclerosis. Neither drug changed the lipid profiles or systolic blood pressure of the mice. Thus, azelnidipine at clinically relevant doses exhibited anti-atherosclerotic effects in monkeys and mice independent of its blood pressure-lowering effects, suggesting that azelnidipine might be as a "vasculoprotective calcium channel blocker".
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PMID:Azelnidipine has anti-atherosclerotic effects independent of its blood pressure-lowering actions in monkeys and mice. 1748 39

Cyclooxygenases (COXs) are crucial rate-limiting enzymes required for the biosynthesis of prostaglandins. COX-2 is an inducible isoform of this enzyme, which is believed to play important roles in the development of atherosclerotic vascular disease. We found that COX-2 expression rapidly increases in response to various signaling events, including activation of the platelet-derived growth factor (PDGF) pathway. Activation of PDGF receptor (PDGFR) in rat aortic vascular smooth muscle cells leads to c-Src-dependent stabilization of COX-2 mRNA requiring an AU-rich region within the 3'-untranslated region of this transcript. This regulation correlates with tyrosine phosphorylation of the RNA-associated protein, CUG-binding protein 2 (CUGBP2), which appears to enhance its interaction with COX-2 mRNA. Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA. We further show that silencing of CUGBP2 with specific small interference RNAs significantly reduces PDGF-dependent induction of COX-2 at both mRNA and protein levels. Furthermore, forced expression of CUGBP2 or constitutively active c-Src leads to stabilization of co-expressed COX-2 mRNA. Finally, in vitro RNA decay assay demonstrates that CUGBP2 is functionally required for the stabilization of COX-2 mRNA. Therefore, our data suggest that tyrosine phosphorylation of CUGBP2 is an important underlying mechanism for the ability of PDGFR/c-Src signaling to control the stability of COX-2 mRNA.
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PMID:Platelet-derived growth factor-induced stabilization of cyclooxygenase 2 mRNA in rat smooth muscle cells requires the c-Src family of protein-tyrosine kinases. 1785 67

Regardless of the type of arterial reconstruction, luminal narrowing (stenosis or restenosis) develops in approximately one third of the vessels. In the past, the focus of research has been on the mechanisms of stenosis (intimal hyperplasia, pathologic remodeling) and pharmacologic approaches to prevention. An alternative approach is to induce intimal atrophy after luminal narrowing has developed, thus limiting treatment to only those patients that develop a problem. This approach to treat established disease by reducing wall mass through induction of cell death and extracellular matrix removal would be particularly useful for treating stenosis in synthetic bypass grafts or stented vessels, in which intimal hyperplasia is the primary mechanism of stenosis. This approach may be applicable as well to other vascular proliferative disorders, such as pulmonary hypertension and chronic transplant arteriopathy. Proof of principle has been shown in experiments with antibodies to platelet-derived growth factor (PDGF) receptors that cause neointimal regression in baboon polytetrafluoroethylene (PTFE) grafts and with angiotensin-converting enzyme inhibitors that induce medial atrophy in hypertensive arteries. Possible molecular targets could include PDGF receptors, A20, and BMP4. Further studies are needed to determine the utility of such a therapeutic approach to vascular disease.
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PMID:Induction of vascular atrophy as a novel approach to treating restenosis. A review. 1795 May 62


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