Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Arginine, the physiologic substrate of nitric oxide synthase, has antiatherogenic properties in animal models of atherosclerosis, and improves endothelial function in hypercholesterolemic humans. Some of these effects may be mediated by increased production of nitric oxide; however, some investigators have postulated a direct antioxidant action related to its aminoguanidine moiety. We aimed therefore, to assess the antioxidant properties of L-arginine. The antioxidant properties of 200 microM L-arginine. 200 microM D-arginine and 200 microM L-glutamate were compared with the powerful antioxidant ascorbate and a control (phosphate-buffered saline). Compounds were tested using four in vitro methods: (1) the Esterbauer technique (which tests the ability of the compounds to scavenge free radicals or chelate transition metals); (2) the effect on the autoxidation of ascorbate; (3) anti-tocopherol mediated peroxidation (which tests the compound's ability to synergize with alpha-tocopherol to prevent mild chemically induced LDL oxidation); and (4) the ability of the compounds to attenuate alpha-tocopherol radical in micellular emulsions (TRAA). The above methods were repeated using the metabolites of the test compounds after incubation with human endothelial cells. Ex vivo studies were then carried out by measuring levels of lipid peroxide production (using HPLC with UV and chemiluminescence detection) in three healthy volunteers before and 2 h after a single 7-g oral dose of L-arginine. By the Esterbauer technique, L-arginine increased lag time by 45% compared to control, as did D-arginine by 50%; L-glutamate had no effect and ascorbate increased lag time by 325%. Neither L-arginine, D-arginine or L-glutamate had significant effects on the autoxidation of ascorbate or anti-tocopherol mediated peroxidation. By the TRAA method, L-arginine had a small effect on preventing the decay of tocopherol. The results were similar for the studies of the compound's metabolites. In ex vivo studies, no changes were seen in lipid peroxide levels following acute dosage with L-arginine. L-Arginine has only weak and non-specific antioxidant effects, suggesting that its major cardioprotective benefits occur through other mechanisms, such as via the nitric oxide pathway.
Atherosclerosis 1999 Oct
PMID:Lack of antioxidant activity of the antiatherogenic compound L-arginine. 1053 88

Monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to inflammatory sites, such as rheumatoid arthritis, atherosclerosis, and asthma, by use of the MCP-1 receptor, CCR2, a member of the G-protein-coupled seven-transmembrane receptor superfamily. These studies identified a family of antagonists, spiropiperidines. One of the more potent compounds blocks MCP-1 binding to CCR2 with a K(d) of 60 nm, but it is unable to block binding to CXCR1, CCR1, or CCR3. These compounds were effective inhibitors of chemotaxis toward MCP-1 but were very poor inhibitors of CCR1-mediated chemotaxis. The compounds are effective blockers of MCP-1-driven inhibition of adenylate cyclase and MCP-1- and MCP-3-driven cytosolic calcium influx; the compounds are not agonists for these pathways. We showed that glutamate 291 (Glu(291)) of CCR2 is a critical residue for high affinity binding and that this residue contributes little to MCP-1 binding to CCR2. The basic nitrogen present in the spiropiperidine compounds may be the interaction partner for Glu(291), because the basicity of this nitrogen was essential for affinity; furthermore, a different class of antagonists, a class that does not have a basic nitrogen (2-carboxypyrroles), were not affected by mutations of Glu(291). In addition to the CCR2 receptor, spiropiperidine compounds have affinity for several biogenic amine receptors. Receptor models indicate that the acidic residue, Glu(291), from transmembrane-7 of CCR2 is in a position similar to the acidic residue contributed from transmembrane-3 of biogenic amine receptors, which may account for the shared affinity of spiropiperidines for these two receptor classes. The models suggest that the acid-base pair, Glu(291) to piperidine nitrogen, anchors the spiropiperidine compound within the transmembrane ovoid bundle. This binding site may overlap with the space required by MCP-1 during binding and signaling; thus the small molecule ligands act as antagonists. An acidic residue in transmembrane region 7 is found in most chemokine receptors and is rare in other serpentine receptors. The model of the binding site may suggest ways to make new small molecule chemokine receptor antagonists, and it may rationalize the design of more potent and selective antagonists.
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PMID:Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. 1077 Sep 25

High cholesterol, especially LDL cholesterol, has been associated with the development of atherosclerotic plaques in arteries. To investigate the changes in cellular substrate metabolism early in the atherogenic process, Sinclair miniature swine were treated for 12 weeks with either a control diet, a high fat diet, or a high fat diet with the addition of alloxan to induce diabetes. The fractional entry into the TCA cycle of 1,2-(13)C-acetate (5 mM), 1-(13)C-glucose (5 mM), and unlabeled, endogenous lipids was determined in control, hyperlipidemic, and diabetic/hyperlipidemic pigs using 13C-isotopomer analysis of glutamate. The diabetic state of the pigs was validated by plasma glucose measurements made after 10 weeks of alloxan treatment for control (65 +/- 6 mg/dL), hyperlipidemic (63 +/- 5 mg/dL), and diabetic/hyperlipidemic (333 +/- 52 mg/dL) pigs. Plasma glucose values did not correlate with the percentage of glucose entry into the TCA cycle (R2 = 0.0819, n = 10). Alterations in the pattern of substrate oxidation were better correlated with changes in plasma lipids (cholesterol and triglycerides) than with changes in plasma glucose. Plasma total cholesterol and total triglyceride levels significantly correlated with changes in acetate metabolism (R2 = 0.7768 and R2 = 0.4787, respectively) and with changes in glucose metabolism (R2 = 0.6067 and R2 = 0.4506, respectively). We conclude that alterations in lipid profile, especially those that were observed in the diabetic milieu, are associated with early changes in vascular smooth muscle oxidative metabolism. These changes in oxidative metabolism may precede alterations in smooth muscle phenotype and, therefore, may play an important role in the early pathogenesis of atherosclerosis.
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PMID:Alterations in the oxidative metabolic profile in vascular smooth muscle from hyperlipidemic and diabetic swine. 1126 71

A common mutation in methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is associated with reduced enzyme activity, a thermolabile enzyme and mild hyperhomocysteinemia, a risk factor for vascular disease. Recently, a second common mutation (1298A-->C; glutamate to alanine) was reported, but this mutation was suggested to increase homocysteine only in individuals who carried the bp677 variant. To evaluate the functional consequences of this mutation, we performed site-directed mutagenesis and in vitro expression. For in vivo assessment of clinical impact, we examined the 1298A-->C genotypes and plasma homocysteine in 198 individuals from the NHLBI Family Heart Study that had previously been assessed for the 677 substitution. Site-directed mutagenesis of the human cDNA was performed to generate enzymes containing each of the two mutations, as well as an enzyme containing both substitutions. Enzyme activity and thermolability were assessed in bacterial extracts. The activity of the wild-type cDNA was designated as 100%; mutant enzymes containing the 1298 and 677 mutations separately had 68% (+/-5.0) and 45% (+/-10.8), respectively, of control activity while the enzyme containing both mutations had 41% (+/-12.8) of control activity. The 1298 mutation was not associated with a thermolabile enzyme. In the Family Heart Study, fasting homocysteine was significantly higher (P<0.05) in individuals heterozygous for both substitutions, compared to individuals who carried only the 677C-->T variant. This study suggests that two variants in MTHFR should be assessed as genetic risk factors for hyperhomocysteinemia.
Atherosclerosis 2001 Jun
PMID:The 1298A-->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. 1139 38

Vascular calcification is common and clinically significant in atherosclerosis and heart failure. It was long believed to be an end-stage process of "passive" mineral precipitation. However, there is now a growing awareness that vascular calcification is a biologically regulated phenomenon. It has many similarities to bone formation, and ectopic bone is a well-documented part of vascular calcification. This implies that alterations in vascular cell differentiation, extensive or localized, are an integral part of vascular calcification. Matrix gamma-carboxylated glutamate (GLA) protein (MGP)-deficient mice develop extensive vascular calcification with replacement of the media by progressively calcifying cartilage. A potential mechanism that explains these findings is MGP interference with bone morphogenetic proteins-potent inducers of cartilage and bone.
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PMID:Insights into the mechanism of vascular calcification. 1147 40

The characteristics of accumulation of autoantibodies (aAbs) on NMDA-type glutamate receptors were studied in blood of patients at different stages (1-4 days, 5-7 days, 8-14 days, up to 28 days) of acute period of ischemic or hemorrhagic stroke. The stability of low values (1.29 +/- 0.31 ng/ml) of the titer of aAbs to NMDA-receptors was revealed in patients with acute cerebral hemorrhage. Two types of titer of Abs to NMDA-receptors were revealed in case with cerebral ischemia. The undulating nature of Abs titer changes was revealed in acute ischemic strokes caused by hypertension and cerebral atherosclerosis (from 2.23 +/- 0.53 ng/ml on the 1-st day with increase up to 3.23 +/- 0.90 ng/ml and up to the 3-4 day), following fluctuations with less pronounced increase on 7-8th day were found out. High titer of aAbs to NMDA-receptors (up to 10.0 ng/ml) were observed on 3-4th day in cases of acute ischemic strokes on the background of chronic alcohol encephalopathy caused by intoxication or dysmetabolism with their retention up to 10-14th day.
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PMID:[Autoantibodies to NMDA-type glutamate receptors in the blood of patients with acute ischemic and hemorrhagic stroke]. 1151 78

Menopause marks the start of a new phase in a woman's life that is associated with a decrease in circulating estrogen levels. Although the average age of women has increased from 50 to nearly 85 years, the average age at menopause has remained essentially constant at 50 years. Thus, women now spend nearly a third of their lives in an estrogen deficient state. This normal aging process in women is associated with increasing health problems such as osteoporosis, cardiovascular disease, neurodegenerative diseases, and cancer. Estrogen replacement therapy (ERT) has been shown to play an important beneficial role in the health and well being of postmenopausal women. Several estrogen preparations are available and among these conjugated equine estrogens (CEE) are most frequently used. The drug CEE, is a complex natural urinary extract of pregnant mare's urine and contains at least 10 estrogens in their sulfate ester form and these are the ring B saturated estrogens: estrone (E(1)), 17beta-estradiol (17beta-E(2)), 17alpha-estradiol (17alpha-E(2)), and the ring B unsaturated estrogens equilin (Eq), 17beta-dihydroequilin (17beta-Eq), 17alpha-dihydroequilin (17alpha-Eq), equilenin (Eqn), 17beta-dihydroequilenin (17beta-Eqn), 17alpha-dihydroequilenin (17alpha-Eqn), and Delta(8)-estrone (Delta(8)-E(1)). All of these estrogens in their unconjugated form are biologically active and can interact with recombinant human estrogen receptor alpha (ERalpha) and beta (ERbeta) with 17beta-estradiol and 17beta-dihydroequilin having the highest affinity for both receptors. A number of the ring B unsaturated estrogens had nearly twofold higher affinity for the ERbeta. The pharmacokinetics of these estrogens in postmenopausal women indicate that the unconjugated estrogens compared to their sulfated forms are cleared more rapidly. The 17-keto estrogens are metabolized to the more potent 17beta-reduced products which are cleared at a slower rate. In postmenopausal women, the extent of 17beta-activation is much higher with the ring B unsaturated estrogens than with ring B saturated estrogens. Oxidized LDL and oxidative stress are thought to contribute to both atherosclerosis and neurodegenerative disorders. Neurons in particular are at a high risk from damage resulting from oxidative stress. In vivo and in vitro studies indicate that the oxidation of LDL isolated from postmenopausal women was inhibited differently by various estrogens and other antioxidants. The unique ring B unsaturated estrogens were the most potent while the red wine component t-resveratrol was the least potent. Studies were designed to explore the cellular and molecular mechanisms that may be involved in the neuroprotective effects of CEE components. The data indicate that the neurotoxic effects of oxidized LDL and glutamate can be inhibited by various estrogens, with the ring B unsaturated estrogens being the most active. These effects are involved in the inhibition of DNA fragmentation and up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic protein Bax. These combined data suggest that some of the neuroprotective benefits associated with long-term estrogen therapy may occur by the above mechanism(s). Because estrogens such as the Delta(8)-estrogens are relatively less feminizing than the classical estrogen 17beta-estradiol, they may be important in the development of more neuro-specific estrogens that will be useful in the prevention of neurodegenerative diseases, such as Alzheimer's and Parkinson disease, in both men and women.
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PMID:Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's. 1294 38

A model system is presented using human umbilical vein endothelial cells (HUVECs) to investigate the role of homocysteine (Hcy) in atherosclerosis. HUVECs are shown to export Hcy at a rate determined by the flux through the methionine/Hcy pathway. Additional methionine increases intracellular methionine, decreases intracellular folate, and increases Hcy export, whereas additional folate inhibits export. An inverse relationship exists between intracellular folate and Hcy export. Hcy export may be regulated by intracellular S-adenosyl methionine rather than by Hcy. Human LDLs exposed to HUVECs exporting Hcy undergo time-related lipid oxidation, a process inhibited by the thiol trap dithionitrobenzoate. This is likely to be related to the generation of hydroxyl radicals, which we show are associated with Hcy export. Although Hcy is the major oxidant, cysteine also contributes, as shown by the effect of glutamate. Finally, the LDL oxidized in this system showed a time-dependent increase in uptake by human macrophages, implying an upregulation of the scavenger receptor. These results suggest that continuous export of Hcy from endothelial cells contributes to the generation of extracellular hydroxyl radicals, with associated oxidative modification of LDL and incorporation into macrophages, a key step in atherosclerosis. Factors that regulate intracellular Hcy metabolism modulate these effects.
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PMID:Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system. 1557 41

Endogenous methylarginines, the catabolism products of proteins containing post-translationally methylated arginine residues, are the modulators of arginine metabolism. Endogenous methylarginines compete with arginine about cationic aminoacid transporter and some of them, e.g. asymmetric dimethylarginine (ADMA) and N-mono-methylarginine (MMA), are competitive inhibitors of nitric oxide synthases. The changes of arginine metabolism, induced by these methylarginines, may have serious consequences, because arginine is the precursor of cell-signalling molecules such as NO, agmatine, glutamate and gamma-aminobutyric acid (GABA) and the regulatory molecules polyamines. ADMA has also prooxidant properties and increases endothelial adhesiveness for monocytes. Asymmetric methyl-arginines induce endothelial dysfunction, which may be reversed by L-arginine supplementation, what is defined as "arginine paradox". The increased plasma concentration of asymmetric methylarginines is induced by hypercholesterolemic or hyperhomocysteinemic diets and by rich sodium chloride intake. The high level of plasma asymmetric methyl-arginines accompanies atherosclerosis, hypertension, chronic renal failure, diabetes, insulin resistence, hyperthyreosis, schizophrenia and sclerosis multiplex. The causes of increased concentration ADMA and MMA in these diseases are just now discovered. The hope in the future is the modulation of methylarginines concentration by regulation of expression and activities of enzymes taking part in the metabolism of these substances, particularly of dimethyl-arginine dimethyl-aminotransferase. The main aim of the present study is to pay attention to possibility of the modulation of asymmetric methyl-arginines concentration, what may be a new way of synthase nitric oxide activity regulation in vivo and may be useful in future therapy of patologies in which synthesis of NO is troubled.
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PMID:[The importance of regulation of endogenous methylarginine concentrations in clinical practice]. 1678 81

Hydroxycut, an herbal supplement not currently defined as a drug, is frequently sold over the counter to increase exercise performance, build muscles, and burn fat. The effects of 8 wk of hydroxycut-induced changes on blood lipid profile in rats fed with either regular or high-fat diet were evaluated. Regardless of fat content in the diet, the doses of hydroxycut used significantly decreased fasting serum concentrations of cholesterol, triacylglycerol (TAG), low-density lipoprotein (LDL) cholesterol, total apolipoprotein B (apo B), and LDL/high-density lipoprotein (HDL) cholesterol ratio. A significant increase in serum blood glucose level was observed with hydroxycut intake in the presence of a high-fat diet. No hydroxycut-related changes in serum activities of serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate dehydrogenase (SGPT), lactate dehydrogenase (LDH), and creatinine phosphokinase (CPK) enzymes were noted, indicating no liver damage occurred. A decrease in liver fat content was observed with hydroxycut intake. The drug did not affect the number and composition of secreted very-low-density lipoprotein (VLDL) particles except for a decrease in VLDL TAG when the fat content in the diet was high. Hydroxycut reduced significantly LDL apo B and LDL TAG and cholesterol concentrations. Hydroxycut increased TAG and cholesterol excretion in feces. A single intragastric food load containing hydroxycut reduced significantly postprandial plasma TAG concentration in a dose-dependent manner. In conclusion, hydroxycut intake in recommended doses exerts a beneficial impact on atherosclerosis, an effect attributed to improved clearance and metabolism of lipoprotein particles, and to a lesser extent to an increased excretion of TAG and cholesterol in the feces. More studies are needed to ensure the safety of long-term use of hydroxycut.
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PMID:Effect of hydroxycut intake on fasted and postprandial lipemia in rats. 1685 87


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