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)

Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL with isolated MPO, an H2O2-generating system, and nitrite (NO2-)-- a major end-product of NO metabolism--resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2-, occurred at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.
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PMID:Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. 1035 64

We evaluated the relationship between plasma fibrinogen concentration and the serum levels of interleukin-6 (IL-6), its soluble receptor, and their complex in patients with type 2 diabetes mellitus. The study comprised 57 patients with type 2 diabetes and 15 normal healthy controls. Serum levels of IL-6, soluble IL-6 receptor (IL-6R), and circulating IL-6/IL-6R complex were determined by enzyme-linked immunosorbent assays. Correlations between the different study parameters and serum IL-6, IL-6R, or IL-6/IL-6R complex levels were determined by multiple linear regression analysis. Any association between the different study parameters and the serum levels of IL-6, IL-6R, or IL-6/IL-6R complex were determined by stepwise linear regression analysis. The serum IL-6 level in diabetic subjects was significantly higher than in normal healthy controls (3.48 +/- 3.29 pg/ml vs 0.784 +/- 0.90 pg/ml, mean +/- SD, respectively, P = 0.0001). The specific optical density of the serum IL-6/IL-6R complex in diabetic patients was also significantly higher than in normal healthy controls, although there was no significant difference in the serum IL-6R level between diabetic patients and controls. The serum IL-6 concentration was correlated significantly with the HbA(1C) level (beta = 0.58, P = 0. 04) by multiple regression analysis. Stepwise regression analysis revealed that the levels of serum IL-6 (F = 8.251), HbA(1C) (F = 1. 08), and serum urea nitrogen (F = 5.603) were associated with the plasma fibrino gen concentration. These results suggest that hyperglycaemia and increased levels of serum IL-6 can increase the plasma fibrinogen concentration, one of the known risk factors for atherosclerosis in patients with type 2 diabetes mellitus.
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PMID:Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. 1043 55

Low protein diet has been proven to retard the progression of chronic renal failure. In this diet, the energy intake depends mainly on fats and carbohydrates instead of protein, and precautions should be taken against increasing risks of both lipid nephrotoxicity and atherosclerosis. In order to assess the adequacy of fat nutrition in a low protein diet for patients with chronic renal failure, we evaluated the total amounts of dietary fat intake, dietary individual fatty acid intake and serum individual fatty acid concentrations in 16 patients, whose mean creatinine clearance was 21.3 +/- 12.1 ml/m, serum creatinine 3.8 +/- 2.2 mg/dl and serum urea nitrogen 41.5 +/- 18.6 mg/dl. The percentage ratio of fat intake to total energy intake was 26.7 +/- 5.2%. The ratio of intake of saturated fatty acids, monounsaturated fatty acids and polyunsaturated fatty acids was 1:2:1.8, and n-6/n-3 was 8.5 +/- 9.3. These were significant correlations between dietary intake and the serum concentrations in both EPA and the ratio of EPA/AA. Consequently, it might be considered that polyunsaturated fatty acids intake should be lowered and patients with chronic renal failure on a low protein diet should be advised about the proper selection of foods containing animal protein and plant-derived oil. It may be beneficial to recommend the intake of more EPA and lowering the ratio of n-6/n-3 intake might be useful in improving the fat nutrition to adequate levels in these patients.
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PMID:[Evaluation of fat nutrition in the energy intake on low protein diets for patients with chronic renal failure]. 1044 93

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
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PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17

Protein nitration and lipid peroxidation are implicated in the pathogenesis of atherosclerosis; however, neither the cellular mediators nor the reaction pathways for these events in vivo are established. In the present study, we examined the chemical pathways available to monocytes for generating reactive nitrogen species and explored their potential contribution to the protein nitration and lipid peroxidation of biological targets. Isolated human monocytes activated in media containing physiologically relevant levels of nitrite (NO(2)(-)), a major end product of nitric oxide ((*)NO) metabolism, nitrate apolipoprotein B-100 tyrosine residues and initiate LDL lipid peroxidation. LDL nitration (assessed by gas chromatography-mass spectrometry quantification of nitrotyrosine) and lipid peroxidation (assessed by high-performance liquid chromatography with online tandem mass spectrometric quantification of distinct products) required cell activation and NO(2)(-); occurred in the presence of metal chelators, superoxide dismutase (SOD), and scavengers of hypohalous acids; and was blocked by myeloperoxidase (MPO) inhibitors and catalase. Monocytes activated in the presence of the exogenous (*)NO generator PAPA NONOate (Z-[N-(3-aminopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2- diolate) promoted LDL protein nitration and lipid peroxidation by a combination of pathways. At low rates of (*)NO flux, both protein nitration and lipid peroxidation were inhibited by catalase and peroxidase inhibitors but not SOD, suggesting a role for MPO. As rates of (*)NO flux increased, both nitrotyrosine formation and 9-hydroxy-10,12-octadecadienoate/9-hydroperoxy-10,12-octadecadieno ic acid production by monocytes became insensitive to the presence of catalase or peroxidase inhibitors, but they were increasingly inhibited by SOD and methionine, suggesting a role for peroxynitrite. Collectively, these results demonstrate that monocytes use distinct mechanisms for generating (*)NO-derived oxidants, and they identify MPO as a source of nitrating intermediates in monocytes.
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PMID:Formation of nitric oxide-derived oxidants by myeloperoxidase in monocytes: pathways for monocyte-mediated protein nitration and lipid peroxidation In vivo. 1055 42

Whereas low plasma levels of carotenes are strongly associated with the elevated risk of atherosclerosis, the reason for this is still unknown. We hypothesized that lipoprotein oxidation in the arterial wall might selectively deplete carotenes, thus explaining the observed effects. In order to assess this hypothesis, we incubated plasma low density lipoprotein (LDL) with different oxidants and measured the consumption of carotenes and tocopherols. We found that when LDL oxidation was induced by nitric oxide, both alpha- and beta-carotene were consumed at a significantly higher relative rate than alpha- or gamma-tocopherol. In contrast, superoxide, peroxynitrite, hypochlorite or transition metal ions were unable to induce selective consumption of carotenes in LDL. These data suggest that the decreased plasma levels of alpha- and beta-carotene frequently measured in atherosclerosis may be related to their preferred consumption by reactive nitrogen species in the arterial wall.
Atherosclerosis 2000 Jan
PMID:Alpha- and beta-carotenes in low density lipoprotein are the preferred target for nitric oxide-induced oxidation. 1058 Jan 74

Diabetic patients typically have not only hyperglycemia but also dyslipidemia. Study of the pathogenic components of the diabetic milieu and mechanisms of accelerated atherosclerosis is hindered by inadequate animal models. A potentially suitable animal model for human diabetic dyslipidemia is the pig, because it carries a large fraction of total cholesterol in low-density lipoprotein (LDL), similar to humans. In this study, male Sinclair miniature pigs were made diabetic by destroying the insulin-producing cells of the pancreas with alloxan and then were fed a high fat and high cholesterol diet for comparison with pigs fed a nondiabetic high fat and high cholesterol diet and control pigs. Diabetic pigs exhibited hyperglycemia, but plasma urea nitrogen, creatinine, and transaminase levels were in the normal range, indicating no adverse effects on kidney and liver function. The lipoprotein profile in diabetic pigs was similar to that found in human diabetic patients and was characterized by hypertriglyceridemia (2.8-fold increase versus control and high fat-fed pigs) and a profound shift of cholesterol distribution into the LDL fraction (81%) versus the distribution in high fat-fed (64%) and control (57%) pigs. LDL particles were lipid-enriched and more heterogeneous in diabetic pigs. Apolipoprotein B was distributed among a much broader spectrum of LDL particles, and apolipoprotein E was partially redistributed from high-density lipoprotein to apolipoprotein B-containing lipoproteins in diabetic pigs. There was little change in apolipoprotein A-I distribution. Diabetic pigs showed several early signs of excess vascular disease. In diabetic pigs, 75% of the coronary artery segments showed contractile oscillations in response to prostaglandin F(2alpha) compared with 25% in high fat-fed pigs and 10% in control pigs. Endothelium-dependent relaxation of brachial arteries was nearly abolished in diabetic pigs but unchanged in high fat-fed versus control pigs. Carotid artery Sudan IV staining for fatty streaks was significantly increased only in diabetic pigs. This porcine model should provide insights into the etiology of human diabetic dyslipidemia and facilitate study of peripheral vascular and coronary artery disease in diabetic patients.
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PMID:Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet. 1059 79

This study was carried out to investigate the relationship between lipoprotein (a) levels and the development of atherosclerosis in chronic renal failure (CRF) patients with the possible role of the liver. Serum Lp (a) levels were measured in samples from 20 CRF patients on hemodialysis (HD), 20 liver cirrhosis (LC) patients, 20 patients having both CRF and LC and undergoing HD, and 20 normal control subjects. Renal function (blood urea nitrogen (BUN) and creatinine), hepatic function (transaminases (ALT and AST), alkaline phosphatase (ALP) and total bilirubin) investigations and serum cholesterol were carried out for all the subjects enrolled in this study. Serum Lp (a) concentration in CRF patients without LC was 87.25 +/- 6.17 mg/dl, which was significantly higher than all the investigated groups (P < 0.001). Lp (a) concentration in patients with both CRF and LC was 24.65 +/- 1.98 mg/dl, which was not significantly different from the controls, but was significantly higher than that in the subjects with LC only (P < 0.001) where the latter group had significantly low Lp (a) values (11.1 +/- 0.99) relative to all the other groups (P < 0.001). Lp (a) correlated positively with cholesterol in all groups except the LC subjects, but did not correlate with age, or renal function in both CRF groups.
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PMID:Serum lipoprotein (a) levels in chronic renal failure and liver cirrhosis patients. Relationship with atherosclerosis. 1068 47

It is clear that smoking causes an increase in free radicals, reactive nitrogen and oxygen species (RNS and ROS, respectively), and that cigarette smoking is associated with increases in the incidence and severity of several diseases including atherosclerosis, cancer, and chronic obstructive lung disease. Although there is still no unequivocal evidence that oxidative stress is a contributor to these diseases or that an increased intake of antioxidant nutrients is beneficial, the observation that smokers have lower circulating levels of some of these nutrients, raises concern. This article discusses the possible links between the observed oxidant-induced damage related to tobacco smoking, effects on cellular mechanisms, and their potential involvement in the causation and enhancement of disease processes.
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PMID:Tobacco-related diseases. Is there a role for antioxidant micronutrient supplementation? 1076 98

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


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