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)

To explore interrelations between folic acid and methionine metabolism in chronic renal insufficiency, we measured plasma amino acids in 21 patients with mean serum creatinine +/- SD of 560 +/- 240 mumol/L, after a ten-hour overnight fast, before and after administration of 5 mg of oral folic acid daily for 15 +/- 6 days. Mean plasma homocysteine was 12.9 +/- 6.8 mumol/L in the patients and 4.2 +/- 0.8 mumol/L in 24 normal controls (P less than .001), and after folic acid administration it declined in the patients to 6.8 +/- 2.8 mumol/L (P less than .0001) in linear proportion (r = .92) to the prefolate homocysteine level. Methionine concentrations were normal in the patients and did not change after folate administration, nor did elevated cysteine and creatinine. Plasma serine was lower (88.3 +/- 17.2 v 121 +/- 25 mumol/L, P less than .41) and declined further to 67.8 +/- 16.4 (P less than .0001) after folate, while prefolate glycine levels increased from 273.3 +/- 61.2 to 313.2 +/- 97.5 mumol/L (P less than .01). Serum and red-cell folate levels were normal in the patients before treatment. The results show that homocysteine levels are increased in chronic renal insufficiency, but may be lowered by folate enhancement of remethylation of homocysteine to methionine. Since elevated plasma homocysteine is associated with premature vascular disease, folic acid may reduce cardiovascular risk in chronic renal insufficiency.
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PMID:Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease. 338 35

We have examined, in normal subjects, the effects of a daily dietary supplement of fish oil concentrate ('maxEPA'), providing 3 g of omega-3 fatty acids, on erythrocyte membrane phospholipids, erythrocyte deformability and blood viscosity. After 3 weeks, incorporation of C20:5 omega 3 into erythrocyte phosphatidyl choline (PC) was greater compared to phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS). After 6 weeks, there was no further increase in total erythrocyte C20:5 omega 3, but its distribution amongst phospholipid subclasses had changed. C20:5 omega 3 had increased further in PE and PS, but decreased in PC. Incorporation of C20:5 omega 3 also occurred into PC, PE and PS. omega-3 Fatty acids were incorporated almost entirely at the expense of C18:2 omega 6, but total unsaturation of phospholipids was increased. This is consistent with increased lipid fluidity, which may be an important determinant of erythrocyte deformability. The same dosage of maxEPA also resulted in a significant increase in erythrocyte deformability and a concomitant reduction in whole blood viscosity. Since plasma viscosity and haematocrit were unchanged it seems likely that the effects on blood rheology were mediated by changes in erythrocyte lipid fluidity. Modification of blood rheology by dietary omega-3 fatty acids is of potential value in the treatment of vascular disease.
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PMID:The effects of dietary omega-3 polyunsaturated fatty acids on erythrocyte membrane phospholipids, erythrocyte deformability and blood viscosity in healthy volunteers. 401 48

Ultrastructural observations in lung tissue implicated an endogenous vascular elastase (EVE), in the pathobiology of pulmonary vascular disease. In experimental rats, increased activity of a 20 kDa serine proteinase related to adipsin precedes the development of sustained pulmonary hypertension and vascular abnormalities. A further increase in activity is related to malignant progression of the disease. A cause and effect relationship was suggested by studies in which elastase inhibitors successfully prevented or retarded progression of pulmonary hypertension. In vitro studies have shown that both serum and endothelial factors induce EVE via tyrosine kinase intracellular signalling. Induction of EVE can release basic fibroblast growth factor from the extracellular matrix in an active form stimulating smooth muscle cell proliferation. Elastase activity was also observed in the process of smooth muscle cell migration and neointimal formation in coronary arteries following experimental cardiac transplantation. An immune/inflammatory response is observed with increased production of cytokines, tumor necrosis factor-alpha and interleukin (IL)-1 beta, reciprocally up-regulating production of fibronectin, a glycoprotein which mediated smooth muscle cell migration. The action of IL-1 beta in inducing fibronectin is facilitated by the production of elastin peptides generated by increased activity of an elastase in the coronary arteries. Our studies suggest that ligation of the elastin binding protein by elastin peptides unmasks IL-1 receptors. Fibronectin also stimulates transendothelial migration of lymphocytes which perpetuates the inflammatory response leading to neointimal formation in this model. Masking integrins on T cells with a decoy synthetic CS-1 (fibronectin) peptide largely prevented transendothelial migration and coronary neointimal formation following cardiac transplant.
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PMID:Elastase and cell matrix interactions in the pathobiology of vascular disease. 877 47

Hyperhomocysteinemia has been recognized as one of the risk factors for atherosclerosis and premature vascular disease. Patients on dialysis and end-stage renal disease also manifest high plasma concentrations of homocysteine. We performed this study to evaluate the effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients. Twenty-three CAPD patients (8 males, 15 females, 49.1 +/- 14.2-years-old) dialyzed for 22.7 +/- 19.2 months participated in the study. Daily 5-mg doses of folic acid supplementation for 4 weeks significantly reduced plasma concentrations of total homocysteine (p < 0.01) and serine (p < 0.001). This observation suggests that the reduction of plasma concentrations of total homocysteine results from activation of homocysteine remethylation to methionine. On the other hand, folic acid supplementation also revealed significant correlations between changes in serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid and changes in plasma concentrations of total homocysteine (r = -0.517, p < 0.05, r = -0.451, p < 0.05, respectively). In addition, serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in 11 CAPD patients with hyperhomocysteinemia (> or = 35 micromol/litter) were significantly lower than those of 12 CAPD patients with normohomocysteinemia (< 35 micromol/litter) (p < 0.05, p < 0.05, respectively). Serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in CAPD patients with hyperhomocysteinemia increased significantly (p < 0.01, p < 0.05, respectively) and reached similar levels of CAPD patients with normohomocysteinemia, while plasma concentrations of total homocysteine decreased after folic acid supplementation. These findings suggest that correction of hyperhomocysteinemia in patients on dialysis produces an increase in unsaturated fatty acids.
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PMID:[Effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients: effects on unsaturated fatty acids]. 951 77

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

The adducts that form when aldehydes modify proteins have been implicated in the pathogenesis of vascular disease and aging. Our previous studies indicated that p-hydroxyphenylacetaldehyde (pHA), the major product of L-tyrosine oxidation by the myeloperoxidase/hydrogen peroxide/chloride system of phagocytes, covalently modifies the epsilon-amino group of lysine residues at sites of inflammation. Here, we report that pHA also reacts with the amino group of synthetic phospholipids and red blood cell model systems. Using fast atom bombardment mass spectrometric analysis of ethanolamine glycerophospholipid or serine glycerophospholipid incubated with pHA and NaBH3CN, we detected products that were consistent with reduced phospholipid Schiff base adducts. We confirmed the reaction of the aldehyde with the amino group through 1H NMR and mass spectrometric analysis of polar headgroups recovered from the modified and reduced parent lipid. When phospholipid model systems and cell membranes were exposed to physiological levels of L-tyrosine and the myeloperoxidase/hydrogen peroxide/chloride system followed by treatment with NaBH3CN, reduced Schiff base adducts of pHA with ethanolamine glycerophospholipid and serine glycerophospholipid (pHA-PE and pHA-PS, respectively) were produced. The reaction required myeloperoxidase, hydrogen peroxide, L-tyrosine, and chloride ion; it was inhibited by catalase or heme poisons, implicating hydrogen peroxide and peroxidase in the pathway. Collectively, these results demonstrate that an aldehyde generated by the myeloperoxidase system of phagocytes can covalently modify the amino groups of phosphatidylethanolamine and phosphatidylserine. Because amino glycerophospholipids are critical components of cell membranes and circulating lipoproteins such as LDL, similar reactions may play important roles in the initiation or progression of disease at sites of inflammation.
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PMID:Synthesis, isolation, and characterization of the adduct formed in the reaction of p-hydroxyphenylacetaldehyde with the amino headgroup of phosphatidylethanolamine and phosphatidylserine. 989 14

A new lipoprotein lipase-like gene has been cloned from endothelial cells through a subtraction methodology aimed at characterizing genes that are expressed with in vitro differentiation of this cell type. The conceptual endothelial cell-derived lipase protein contains 500 amino acids, including an 18-amino acid hydrophobic signal sequence, and is 44% identical to lipoprotein lipase and 41% identical to hepatic lipase. Comparison of primary sequence to that of lipoprotein and hepatic lipase reveals conservation of the serine, aspartic acid, and histidine catalytic residues as well as the 10 cysteine residues involved in disulfide bond formation. Expression was identified in cultured human umbilical vein endothelial cells, human coronary artery endothelial cells, and murine endothelial-like yolk sac cells by Northern blot. In addition, Northern blot and in situ hybridization analysis revealed expression of the endothelial-derived lipase in placenta, liver, lung, ovary, thyroid gland, and testis. A c-Myc-tagged protein secreted from transfected COS7 cells had phospholipase A1 activity but no triglyceride lipase activity. Its tissue-restricted pattern of expression and its ability to be expressed by endothelial cells, suggests that endothelial cell-derived lipase may have unique functions in lipoprotein metabolism and in vascular disease.
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PMID:Cloning of a unique lipase from endothelial cells extends the lipase gene family. 1031 35

Flavonoids are a group of naturally-occurring phenolic compounds in the plant kingdom, and many flavonoids are found with vascular protective properties. Nevertheless how the protective response is exerted by flavonoids is not well characterized. In view of the nuclear factor-kappaB (NFkappaB) may play a central role in the initiation of atherosclerosis, prevention of the activation of NFkappaB represents an important role in protecting vascular injury. In this study, the effects of flavonoids on NFkappaB/inhibitor-kappaB (IkappaB) system in ECV304 cells activated with tumor necrosis factor-alpha (TNFalpha) were examined. We investigated the inhibitory action of six flavonoids on IkappaB kinase (IKK) activity, an enzyme recently found to phosphorylate critical serine residues of IkappaB for degradation. Of six flavonoids tested, myricetin was found to strongly inhibit IKK kinase activity, and prevent the degradation of IkappaBalpha and IkappaBbeta in activated endothelial cells. Furthermore, myricetin was also found to inhibit NFkappaB activity correlated with suppression of monocyte adhesion to ECV304 cells. Therefore we conclude that flavonoids may be of therapeutic value for vascular disease through down regulation of NFkappaB/IkappaB system.
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PMID:Suppression of TNFalpha-mediated NFkappaB activity by myricetin and other flavonoids through downregulating the activity of IKK in ECV304 cells. 1044 Sep 30

Increased expression of the glycoprotein tenascin-C (TN) is associated with progression of clinical and experimental pulmonary hypertension. In cultured smooth muscle cells (SMCs) TN is induced by matrix metalloproteinases (MMPs) and amplifies the proliferative response to growth factors. Conversely, suppression of TN leads to SMC apoptosis. We now report that hypertrophied rat pulmonary arteries in organ culture, which progressively thicken in association with cell proliferation and matrix accumulation, can be made to regress by inhibiting either serine elastases or MMPs. This effect is associated with reduced TN, suppression of SMC proliferation, and induction of apoptosis. Selective repression of TN by transfecting pulmonary arteries with antisense/ribozyme constructs also induces SMC apoptosis and arrests progressive vascular thickening but fails to induce regression. This failure is related to concomitant expansion of a SMC population, which produces an alternative cell survival alpha(v)beta(3) ligand, osteopontin (OPN), in response to pro-proliferative cues provided by a proteolytic environment. OPN rescues MMP inhibitor-induced SMC apoptosis, and alpha(v)beta(3) blockade induces apoptosis in hypertrophied arteries. Our data suggest that proteinase inhibition is a novel strategy to induce regression of vascular disease because this overcomes the pluripotentiality of SMC-matrix survival interactions and induces coordinated apoptosis and resorption of matrix.
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PMID:Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. 1061 58

Recent evidence suggests that an increased plasma concentration of the sulphur amino acid homocysteine is a risk factor for the development of vascular disease. The tissue(s) responsible for homocysteine production and export to the plasma are not well known. However, given the central role of the liver in amino acid metabolism, we developed a rat primary hepatocyte model in which homocysteine (and cysteine) production and export were examined. The dependence of homocysteine export from incubated hepatocytes on methionine concentration fitted well to a rectangular hyperbola, with half-maximal homocysteine export achieved at methionine concentrations of approx. 0.44 mM. Hepatocytes incubated with 1 mM methionine and 1 mM serine (a substrate for the transulphuration pathway of homocysteine removal) produced and exported significantly less homocysteine (25-40%) compared with cells incubated with 1 mM methionine alone. The effects of dietary protein on homocysteine metabolism were also examined. Rats fed a 60% protein diet had a significantly increased total plasma homocysteine level compared with rats fed a 20% protein diet. In vitro effects of dietary protein were examined using hepatocytes isolated from animals maintained on these diets. When incubated with 1 mM methionine, hepatocytes from rats fed the high protein diet exported significantly more homocysteine compared with hepatocytes from rats fed the normal protein diet. Inclusion of serine significantly lowered homocysteine export in the normal protein group, but the effect was more marked in the high protein group. In vivo effects of serine were also examined. Rats fed a high protein diet enriched with serine had significantly lower total plasma homocysteine (25-30%) compared with controls. These data indicate a significant role for the liver in the regulation of plasma homocysteine levels.
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PMID:Characterization of homocysteine metabolism in the rat liver. 1097 Jul 80


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