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)

1. Nitric oxide (NO) plays a fundamental role in the vasculature because of its diverse influence in vascular protection, including its well-reported antiproliferative, anti-inflammatory, antithrombotic and vasodilator effects. In many vascular disease states, NO production is reduced as a result of endothelial dysfunction, in part caused by a decrease in substrate (L-arginine) availability. 2. The role of L-arginine and other amino acids important in nitrogen balance has been re-examined in the context of their effects on vascular health. The metabolism of L-arginine is complex because it is involved in a plethora of other pathways, such as urea, creatine and agmatine production. L-Arginine supplementation in patients with vascular disease is well reported to benefit patients therapeutically because of its effect on both NO-dependent and -independent mechanisms. 3. L-Arginine availability depends on the flux of other amino acids in the body, including L-glutamine, L-glutamate, L-ornithine, L-citrulline and L-lysine. The role of L-methionine and homocystine and their effect on NO also play an influential role in the body. 4. Recent data suggest that the key enzyme involved in the L-arginine-urea cycle, arginase, is coexpressed in NO-producing cells in the vasculature. In the present review, we examine the potential role of arginase as a therapeutic target for vascular health.
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PMID:Amino acids, arginase and nitric oxide in vascular health. 1644 92

Epidemiologic and experimental observations suggest high density lipoprotein (HDL) has a protective effect against atherothrombotic vascular disease. These findings have stimulated considerable interest to promote HDL as a potential therapeutic strategy. Several exciting therapeutic strategies have recently emerged and currently are the focus of intense research interest. One approach is the direct administration of HDL or its components such as apolipoprotein A-I (apoA-I). Recently, much attention has focused on a naturally occurring variant of apoA-I, apoA-I(Milano) (apoA-IM) characterized by a cysteine for arginine substitution that is associated with low rates of vascular disease and significant longevity in its carriers, despite markedly reduced HDL and elevated triglyceride levels. The mutation alters the characteristics of the protein resulting in apoA-IM being functionally more effective than normal apoA-I. A number of animal and laboratory studies have demonstrated significant antiatherogenic, antiproliferative, antirestenotic, antiplatelet, antithrombotic, antiinflammatory, and antioxidant properties of apoA-IM. Furthermore, apoA-IM has been shown to promote reverse cholesterol transport, improve endothelial dysfunction and induce rapid mobilization of tissue cholesterol resulting in regression and alteration of plaque composition in animal models of atherosclerosis. Recently, a pilot clinical trial of recombinant apoA-IM demonstrated significant and rapid regression of atherosclerosis as measured by intravascular ultrasound in patients with acute coronary syndromes. These promising data provide the rationale for the development of reconstituted HDL utilizing recombinant apoA-IM as a potential therapeutic approach for atherothrombotic vascular disease in humans.
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PMID:ApoA-I Milano/phospholipid complexes emerging pharmacological strategies and medications for the prevention of atherosclerotic plaque progression. 1650 67

Nitric oxide (NO) plays a key role in vascular homeostasis. Accurate measurement of NO production by endothelial nitric oxide synthase (eNOS) is critical for the investigation of vascular disease mechanisms using genetically modified animal models. Previous assays of NO production measuring the conversion of arginine to citrulline have required homogenisation of tissue and reconstitution with cofactors including NADPH and tetrahydrobiopterin. However, the activity and regulation of NOS in vivo is critically dependant on tissue levels of these cofactors. Therefore, understanding eNOS regulation requires assays of NO production in intact vascular tissue that do not depend on the addition of exogenous cofactors and have sufficient sensitivity and specificity. We describe a novel technique, using radiochemical detection of arginine to citrulline conversion, to measure NO production within intact mouse aortas, without exogenous cofactors. We demonstrate the presence of arginase activity in mouse aortas which has the potential to confound this assay. Furthermore, we describe the use of N-hydroxy-nor-L-arginine (nor-NOHA) to inhibit arginase and permit specific detection of NO production in intact mouse tissue. Using this technique we demonstrate a 2.4-fold increase in NO production in aortas of transgenic mice overexpressing eNOS in the endothelium, and show that this technique has high specificity and high sensitivity for detection of in situ NO synthesis by eNOS in mouse vascular tissue. These results have important implications for the investigation of NOS regulation in cells and tissues.
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PMID:Radiochemical HPLC detection of arginine metabolism: measurement of nitric oxide synthesis and arginase activity in vascular tissue. 1664 84

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
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PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97

Nitric oxide (NO) is a molecule that has gained recognition as a crucial modulator of vascular disease. NO has a number of intracellular effects that lead to vasorelaxation, endothelial regeneration, inhibition of leukocyte chemotaxis, and platelet adhesion. Endothelium damage induced by atherosclerosis leads to the reduction in bioactivity of endothelial NO synthase (eNOS) with subsequent impaired release of NO together with a local enhanced degradation of NO by increased generation of reactive oxygen species with subsequent cascade of oxidation-sensitive mechanisms in the arterial wall. Many commonly used vasculoprotective agents have their therapeutic actions through the production of NO. L-Arginine, the precursor of NO, has demonstrated beneficial effects in atherosclerosis and disturbed shear stress. Finally, eNOS gene polymorphism might be an additional risk factor that may contribute to predict cardiovascular events. However, further studies are needed to understand the possible clinical implications of these correlations.
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PMID:Nitric oxide and atherosclerosis: an update. 1668 13

Embryonic stem (ES) cells are highlighted as promising cell sources for regenerative medicine. Here, we focused on providing the platform that forced ES cells to reproduce the vascular organization process, leading to efficiency and safety evaluation as preclinical testing of biological agents. Murine ES cell-derived embryoid bodies on matrigel, but not collagen or gelatin, could be differentiated into sprouting blood vessels without the addition of growth factors. The expression of endothelial cell marker CD31 and smooth muscle marker alpha-smooth muscle actin was partially colocalized and started to increase 7 days after culture on matrigel, accompanied by the induction of a number of growth factors, such as vascular endothelial growth factor, fibroblast growth factor-2, hepatocyte growth factor, transforming growth factor-beta, and angiopoietin-1. Moreover, notch-related genes, such as Del1 or Del4 (delta-like 1/4) and hey1 or hey2 (hairy/enhancer of split related TRPW motif 1/2), were upregulated in a similar time course. The treatment of neutralizing antibodies against these growth factors failed to inhibit the differentiation into the sprouting blood vessels, whereas arginine-glycine-aspartic peptide, a selective inhibitor for the alphavbeta3-integrins, did inhibit differentiation. An anticancer drug to inhibit angiogenesis, TNP-470, also blocked the vascular formation in this model. ES cells could reproduce the vascular organization process on the biosynthetic scaffolds, such as matrigel, without the addition of growth factors. In the future, a human ES-based tissue model would be an optional tool for the screening of pharmaceutical drugs for vascular disease.
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PMID:Model of vasculogenesis from embryonic stem cells for vascular research and regenerative medicine. 1675 88

Endothelial dysfunction is a hallmark of cardiovascular disease, and the l-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with l-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (P = 0.01) than nonsmokers, whereas citrulline (17%; P < 0.05) and N-hydroxy-l-arginine (34%; P < 0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-l-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial l-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease.
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PMID:Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress. 1692 96

Chronic vascular disease in diabetes is associated with disruption of extracellular matrix (ECM) interactions with adherent endothelial cells, compromising cell survival and impairing vasculature structure. Loss of functional contact with integrins activates anoikis and impairs angiogenesis. The metabolic dysfunction underlying this vascular damage and disruption is unclear. Here, we show that increased modification of vascular basement membrane type IV collagen by methylglyoxal, a dicarbonyl glycating agent with increased formation in hyperglycemia, formed arginine-derived hydroimidazolone residues at hotspot modification sites in RGD and GFOGER integrin-binding sites of collagen, causing endothelial cell detachment, anoikis, and inhibition of angiogenesis. Endothelial cells incubated in model hyperglycemia in vitro and experimental diabetes in vivo produced the same modifications of vascular collagen, inducing similar responses. Pharmacological scavenging of methylglyoxal prevented anoikis and maintained angiogenesis, and inhibition of methylglyoxal metabolism with a cell permeable glyoxalase I inhibitor provoked these responses in normoglycemia. Thus, increased formation of methylglyoxal and ECM glycation in hyperglycemia impairs endothelial cell survival and angiogenesis and likely contributes to similar vascular dysfunction in diabetes.
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PMID:Increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by RGD and GFOGER motif modification. 1680 64

The rationale of this study is based on the fact that, both proteinuria and elevated asymmetric dimethyl arginine (ADMA) levels have been linked to the progression of vascular disease. Currently, there is not enough knowledge about any association between the levels of proteinuria and ADMA levels. Seventy-eight non-diabetic patients (42 men, 36 women, mean age of 26.1+/-5.2 years) with proteinuria having normal glomerular filtration rate were enrolled along with 38 healthy subjects (20 men, 18 women, mean age of 26.9+/-5.9 years). Proteinuria was below 3.5 g/day in 40 patients and above 3.5 g/day in 38 patients. Both groups had similar age, gender, and body mass index distributions. Serum ADMA, symmetric dimethyl arginine (SDMA), immunoreactive insulin, and high sensitivity C reactive protein (hsCRP) levels were measured. Insulin resistance was determined by homeostasis model assessment (HOMA). Serum ADMA, SDMA, insulin, hsCRP levels, and HOMA indexes were significantly higher in patients than in healthy control subjects. The above parameters were higher in the nephrotic range proteinuria group when compared to patients having protein levels below 3.5 g/day. There were significant correlations between the levels of proteinuria and the above parameters. According to the regression analysis, levels of proteinuria and hsCRP were significant determinants of serum ADMA levels. Our results indicate that, independent of other risk factors, ADMA is directly associated with proteinuria. Further studies are recommended to find out whether elevated ADMA levels are implicated in the high cardiovascular risk of proteinuric nephropathies.
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PMID:ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease. 1682 Jul 89

Vascular diseases are characterized by impairment of endothelial-derived nitric oxide (NO) bioactivity and increased vascular levels of hydrogen peroxide (H(2)O(2)). Here we examined the implications of H(2)O(2) for agonist-stimulated endothelial NO bioactivity in rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC). Vessels pre-treated with H(2)O(2) exhibited impaired endothelial-dependent relaxation induced by acetylcholine or calcium ionophore. In contrast, H(2)O(2) had no effect on endothelium-independent relaxation induced by a NO donor, indicating a defect in endothelium-derived NO. This defect was not related to eNOS catalytic activity; treatment of PAEC with H(2)O(2) enhanced agonist-stimulated eNOS activity indicated by increased eNOS phosphorylation at Ser-1177 and de-phosphorylation at Thr-495 and enhanced conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline that was prevented by inhibitors of Src and phosphatidylinositol-3 kinases. Despite activating eNOS, H(2)O(2) impaired endothelial NO bioactivity indicated by attenuation of the increase in intracellular cGMP in PAEC stimulated with calcium ionophore or NO. The decrease in cGMP was not due to impaired guanylyl cyclase as H(2)O(2) treatment increased cGMP accumulation in response to BAY 41-2272, a NO-independent activator of soluble guanylyl cyclase. At concentrations that impaired endothelial NO bioactivity H(2)O(2) increased intracellular oxidative stress and size of the labile iron pool in PAEC. The increase in oxidative stress was prevented by the free radical scavenger's tempol or tiron and the iron chelator desferrioxamine and these antioxidants reversed the H(2)O(2)-induced impairment of NO bioactivity in PAEC. This study shows that despite promoting eNOS activity, H(2)O(2) impairs endothelial NO bioactivity by promoting oxidative inactivation of synthesized NO. The study highlights another way in which oxidative stress may impair NO bioactivity during vascular disease.
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PMID:Hydrogen peroxide restrains endothelium-derived nitric oxide bioactivity -- role for iron-dependent oxidative stress. 1686 1


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