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)

Platelet aggregation was studied in 14 diabetic children with no signs of angiopathy and in 14 healthy matched control children. The magnitude of the platelet shape change after ADP stimulation was decreased in diabetic patients while the maximal aggregation after ADP and low dose collagen was significantly higher than in healthy control children. In 28 diabetic children the platelet shape change after ADP stimulation was positively correlated with the serum concentration of apolipoprotein A-I and negatively correlated with serum triglyceride concentration. The ratio between the fatty acids 20:3/20:4 in cholesterol esters was strongly correlated with the relative incidence of irreversible aggregation (p less than 0.001) and with the magnitude of the maximal aggregation (p less than 0.01) after ADP stimulation (3.3 mumol/l). The ratio between the polyunsaturated and saturated fatty acids in the triglyceride fraction was negatively correlated to the maximal aggregation after collagen stimulation (10 mg/l). This study shows tha platelet aggregation is increased early in the course of diabetes in childhood. It suggests that the abnormalities in platelet aggregation pattern in diabetic patients are related to several of the lipid factors associated with an increased risk of atherosclerosis.
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PMID:Increased platelet aggregability in diabetic children: relation to serum lipid and fatty acid composition. 665 42

Apolipoprotein A-IMilano (apoA-IM), a natural variant of apolipoprotein A-I (apoA-I), confers to the carriers a significant protection against vascular disease. The antiatherogenic activity of a recombinant disulfide-linked apoA-IM dimer (rA-IM/A-IM) was analyzed in vivo by evaluating its effect on neointimal formation induced by periarterial manipulation in 1% cholesterol-fed rabbits. A flexible collar was applied around the carotid artery 21 days after the beginning of the dietary regimen, and animals were killed 10 days later. Rabbits were injected five times with reconstituted high-density lipoprotein containing egg phosphatidylcholine (EPC) and rA-IM/A-IM (119 mg EPC + 40 mg protein per dose) or with EPC liposomes (119 mg EPC per dose) beginning either 5 days before or at the day of collar positioning. Neither treatment affected plasma cholesterol levels. A significant intimal thickening was observed in control animals; the intima-to-media (I/M) ratio was 0.63 +/- 0.11 versus 0.03 +/- 0.05 for the sham-operated contralateral arteries. Neointimal formation was markedly inhibited in animals pretreated with rA-IM/A-IM before lesion induction (I/M, 0.26 +/- 0.19) but not in those in which treatment began the day of collar insertion (I/M, 0.74 +/- 0.14). EPC liposomes did not affect neointimal formation (I/M, 0.50 +/- 0.14 and 0.51 +/- 0.07 in the two treatment groups). Proliferation of smooth muscle cells, assessed by direct incorporation of bromo-2'-deoxyuridine (BrdU) into replicating DNA, was reduced by approximately 30% and 75% in the intimal and medial tissues of rA-IM/A-IM-pretreated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant apolipoprotein A-IMilano dimer inhibits carotid intimal thickening induced by perivascular manipulation in rabbits. 785 87

Most known mutations underlying human lipoprotein abnormalities affect the protein coding sequence of the gene involved. Mutations in the regulatory regions-promoters, enhancers, binding sites for transcription factors and other elements-may markedly alter the transcription efficiency of lipid-regulatory genes, and may thus cause an inherited defect of lipoprotein metabolism. Reported examples include mutations of the promoters of the human LDL and lipoprotein lipase genes. Common variation of the DNA sequence in the promoter region, such as that occurring in the human apolipoprotein A-I and plasminogen activator inhibitor(-1) genes, may account for subtle differences in serum lipid levels and risk of atherosclerotic vascular disease in the general population.
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PMID:Regulatory mutations in human lipoprotein disorders and atherosclerosis. 874 97

Recent studies in man and human apolipoprotein A-I transgenic animals emphasize the significance of apolipoprotein A-I and high density lipoprotein in antiatherogenesis. Several drugs and other compounds, e.g. phenobarbital, gemfibrozil, fenofibrate, prednisone, estrogen and alcohol, induce apolipoprotein A-I synthesis. They commonly produce serum lipoprotein patterns typical of a low risk of coronary heart disease, and many of them have been found to prevent atherogenesis, reduce coronary heart disease mortality and increase survival. These compounds act against atherosclerosis by using one or several mechanisms that include overexpression of the apolipoprotein A-I gene with an increase in serum apolipoprotein A-I and high density lipoprotein and promotion of reverse cholesterol transport, upregulation of the low density lipoprotein receptor gene with a decrease in serum apolipoprotein B and low density lipoprotein, maintenance of endothelial cell function and protection against thrombosis. They have been found to raise high density lipoprotein cholesterol and apolipoprotein A-I together with a decrease in cholesterol ester transfer protein activity, and to induce hepatic cholesterol 7 alpha-hydroxylase and cholesterol and bile acid elimination from the body. By raising the activities of apolipoprotein A-I/high density lipoprotein-associated paraoxonase and other antioxidative enzymes, the inducers have the capacity to prevent atherogenesis in arterial walls through inhibition of the oxidative modification of low density lipoprotein. Other antiatherogenic vascular actions of high density lipoprotein include interference with low density lipoprotein aggregation and uptake by endothelial cells, and competition with low density lipoprotein for endothelial-localized low density lipoprotein receptors. Apolipoprotein A-I/high density lipoprotein beneficially enhances fibrinolysis, decreases platelet aggregation, increases prostacyclin production and stabilization and prevents atherogenic immune and inflammatory responses. This gene activation or microsomal induction can prevent atherosclerosis and is a basis for tailoring effective new agents and optimal non-invasive therapy against atherosclerotic vascular disease to promote health and enhance longevity.
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PMID:Gene activation, apolipoprotein A-I/high density lipoprotein, atherosclerosis prevention and longevity. 929 1

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

There is a substantial body of evidence showing that moderate alcohol consumption is associated with a reduced risk of cardiovascular morbidity and mortality. One of the factors thought to contribute to this reduction in risk is an increase in the level of high-density lipoproteins (HDL) correlated with alcohol consumption. However, HDL levels are elevated in heavy drinkers, but their risk of vascular disease is greater compared with that of moderate drinkers. Ethanol at concentrations observed in heavy drinkers and alcoholics may directly act on HDL and apolipoproteins and in turn modify cholesterol efflux. In this paper, we show that ethanol significantly inhibited cholesterol efflux from fibroblasts to HDL and to apolipoprotein A-I (apoA-I) complexed with phosphatidylcholine (PC). Ethanol significantly inhibited binding of PC to apoA-I, inhibited incorporation of cholesterol only when apoA-I contained PC, and did not alter incorporation of cholesterol into HDL. ApoA-I structure was altered by ethanol as monitored by steady-state fluorescence polarization of tryptophan residues. The absence of ethanol effects on incorporation of cholesterol into HDL versus inhibition of cholesterol incorporation into the apoA-I-PC complex suggests that the effects of ethanol on cholesterol efflux mediated by HDL involve interaction with the cell surface and that efflux mediated by the apoA-I-PC complex is a combination of aqueous diffusion and contact with the cell surface. In addition, effects of ethanol on apoA-I suggest that pre-beta-HDL or lipid-free apoA-I may be more perturbed by ethanol than mature HDL, and such effects may be pathophysiological with respect to the process of reverse cholesterol transport in heavy drinkers and alcoholics.
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PMID:Cholesterol efflux to high-density lipoproteins and apolipoprotein A-I phosphatidylcholine complexes is inhibited by ethanol: role of apolipoprotein structure and cooperative interaction of phosphatidylcholine and cholesterol. 1095 52

Atherosclerotic vascular disease is the leading cause of mortality and morbidity in much of the Western world. Although advances in lifestyle and risk factor modification, pharmacotherapy, endovascular interventions and surgery have considerably improved clinical outcome, 40 - 50% of adverse cardiovascular events continue to occur despite current strategies. A number of new targets for therapeutic exploitation are currently being investigated that include, among others, apolipoprotein A-I, the major structural component of high density lipoprotein (HDL) particle. The strong negative relationship between HDL-cholesterol levels and coronary heart disease in epidemiological studies, as well as data from experimental models suggest that HDL-based therapies could be an important new paradigm for prevention, treatment and reversal of atherosclerotic vascular disease.
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PMID:Focus on HDL: a new treatment paradigm for athero-thrombotic vascular disease. 1106 Jul 98

The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 age- and race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had >80% carotid stenosis, and the 106 controls had <15%. Two PON1 substrate hydrolysis rates (paraoxon [POase] and diazoxon [DZOase]) were significantly lower in cases than in controls and were significant predictors of CAAD by use of logistic regression (POase, P=0.005; DZOase, P=0.019). DZOase predicted vascular disease independently of lipoprotein profile, high density lipoprotein subfractions, apolipoprotein A-I, and smoking. PON1-192 and PON1-55 genotypes or haplotypes did not predict case-control status unless the activity phenotype was also included as a predictor by use of logistic regression. When phenotype was included as a predictor, PON1-192 and PON1-55 genotypes or combined haplotypes were significant predictors (P<0.05). In conclusion, examining PON1-192 and/or PON1-55 genotypes alone may mistakenly lead to the conclusion that there is no role of PON1 in CAAD. These results support the benefit of a "level crossing" approach that includes intervening phenotypes in the study of complexly inherited disease.
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PMID:Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype. 1107 50

Apolipoprotein A-I(Milano) (AIM), a natural variant of human apolipoprotein A-I, confers to carriers a significant protection against vascular disease. In previous studies, administration of recombinant AIM-phospholipid (AIM-PL) complexes to hypercholesterolemic rabbits markedly inhibited neointimal formation after arterial injury; moreover, repeated injections of AIM-PL in apoE-deficient mice significantly reduced atherosclerosis progression. The objective of the present study was to determine if a single localized infusion of AIM-PL complexes administered directly to atheromatous lesions could promote plaque regression. Lipid-rich, atheromatous plaques were generated at both common carotid arteries of 25 rabbits by applying a perivascular electric injury, followed by 1.5% cholesterol diet for 90 days. Rabbits were infused with either saline, phospholipid vesicles, or 3 different AIM-PL doses (250, 500, or 1000 mg of protein) delivered through an intravascular ultrasound (IVUS) catheter positioned at the origin of the right carotid. The lesions at the left carotid artery were therefore exposed to the agents systemically. Infusion of AIM-PL at the 2 highest doses caused reduction of right carotid artery plaque area by the end a 90-minute infusion as assessed by IVUS analysis. Plaque area regression was confirmed by histology in carotid arteries receiving direct (500 and 1000 mg doses) and systemic (500 mg dose) delivery, 72 hours after the start of the treatment. Plaque lipid content was associated with significant and similar decreases in Oil Red O staining in both arteries. These results suggest AIM-PL complexes enhanced lipid removal from arteries is the mechanism responsible for the observed plaque changes.
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PMID:Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. 1201 63

Malnutrition in end-stage renal disease (ESRD) is characterized by hypoalbuminemia, decreased serum creatinine and prealbumin, and decreased subjective global assessment (SGA) scores. Markers of malnutrition predict mortality and correlate closely with inflammatory markers, including serum cytokines and acute phase proteins. After multiple regression analysis, markers of inflammation become stronger predictors of mortality than nutritional markers, suggesting that malnutrition is a result of inflammation. The etiology of inflammation is variable and includes vascular access infection, bioincompatible dialyzers, back filtration of nonsterile dialysate, periodontal disease, urinary tract infections, and other pyogenic infections. Renal failure also may serve to promote inflammation through protein carbonylation. Differences in care patterns of ESRD patients and genetics may contribute to inflammation as evidenced by lower levels of C-reactive protein (CRP) in Asian populations. Inflammation results in loss of muscle mass and hypoalbuminemia as a consequence of its decreased synthesis and increased catabolism. Vascular disease occurs partly because of changes in lipoprotein structure and function, including oxidation of low-density lipoprotein (LDL) and modification of high-density lipoprotein (HDL) by serum amyloid A (SAA) and loss of apolipoprotein A-I. Leukocyte adhesion is promoted by changes in endothelial structure and function, whereas plasma proteins associated with cardiovascular disease (fibrinogen, lipoprotein[a]; SAA) are increased. Consequences of inflammation in ESRD patients include muscle wasting, erythropoetin resistance, and vascular disease. Whereas improvements in nutrition can increase serum albumin and creatinine levels, identification and removal of the underlying cause of inflammation should be one treatment goal.
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PMID:Inflammation in ESRD: causes and potential consequences. 1267 42


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