Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoprotein(a) (Lp[a]) represents a class of plasma lipoprotein particles that have overall characteristics similar to low-density lipoproteins but distinct from them by having apolipoprotein B100 linked to apolipoprotein(a) by disulfide bridge(s). This protein has recently been shown to have a striking amino acid sequence homology with plasminogen, a serine protease zymogen that on activation to plasmin promotes the conversion of fibrinogen to fibrin. The high incidence of Lp(a) in the plasma of patients with cardiovascular disease has been noted by many investigators. The new knowledge being rapidly acquired on the structure of Lp(a) should facilitate the understanding of the mechanism of its atherogenicity and perhaps shed light on its possible physiologic role.
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PMID:Lipoprotein(a). A potential bridge between the fields of atherosclerosis and thrombosis. 297 66

A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.
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PMID:Familial apolipoprotein E deficiency. 377 93

The aim was to identify genetic determinants for the development of hyperlipidemia and/or atherosclerosis. The present set of studies demonstrates for the first time the clinical expression (phenotype) of a newly discovered monogenic disorder named Familial Defective Apolipoprotein B-100 (FDB). FDB is caused by a G to A mutation in the binding protein (apolipoprotein B-100) for the cholesterol-rich low density lipoprotein (LDL), such that the affinity of LDL to the LDL receptor is severely reduced. In all 135 individuals with FDB from 56 families and 8 different countries, including Denmark, are described. On average, the effect of the FDB mutation was to increase plasma and LDL cholesterol in both men and women by about 3 mmol/l; at age 55 the average plasma cholesterol of men and women with FDB was 9.4 mmol/l and 8.9 mmol/l, respectively. A sharp rise in frequency of coronary artery disease as a function of age in both FDB males and females was comparable to that found in Familial Hypercholesterolemia (FH). At the age of 60, about 70% of both men and women with FDB had coronary artery disease; at the same age approximately 40% had tendon xanthomas, and 35% had arcus corneae, irrespective of gender. Surprisingly, the frequencies of arcus corneae were not strikingly higher than those found in the general population sample from the Copenhagen City Heart Study. Only few patients with FDB had xanthelasmas. Finally, the frequency of this mutation was estimated at 1/500-1/700 in the general population, which is equivalent to that of clinical FH. All in all the results suggest FDB to be a severe genetic disorder with early penetrance, associated with substantial elevations in plasma and LDL cholesterol and with an increased frequency of premature coronary artery disease and of tendon xanthomas. For comparison, a number of common polymorphisms in the 5'-flanking region of the insulin gene, in the apoB gene and in the apoAI-CIII-AIV gene cluster, associated with minor effects on hyperlipidemia and/or cardiovascular disease are also examined.
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PMID:Rare and common mutations in hyperlipidemia and atherosclerosis. With special reference to familial defective apolipoprotein B-100. 765 81

A new program for lipoprotein characterization is outlined where capillary electrophoresis (CE) plays a central role in the analysis of intact lipoprotein serum components and the apoprotein domains. The first characterization step involves separation and particle density analysis of very low-, low-, and high-density lipoprotein fractions (VLDL, LDL, HDL) by ultracentrifugation and image analysis. VLDL, HDL, and LDL fractions are analyzed by capillary electrophoresis. Sodium dodecyl sulfate (SDS) at low concentrations in the background electrolyte used in the CE analysis is incorporated into the lipoprotein particle without appreciable delipidation, as determined by ultracentrifuge particle density analysis. Increasing the concentration of SDS results in extensive delipidation, resulting in the release of apoproteins (apo) which are detected as components of the electropherogram. Apo B-100 is detected in the delipidated VLDL and LDL fractions along with micelles of the lipids. Micelles from LDL delipidation have uniform charge densities. Apo A-I and A-II are detected in the HDL fraction. A new method for lipoprotein delipidation is introduced where the lipoprotein fraction is adsorbed on a reversed-phase hydrophobic cartridge. Delipidation and recovery of the apoprotein fractions is made by serial elutions with acetonitrile. CE of the lipid-free apoprotein mixture shows the presence of apoC-I,II,III and apoE in the VLDL fraction, and apoA-I,II apoC-I and apoE in the HDL fraction. Electrospray ionization mass spectrometry analysis gives the isoform distribution for each apoprotein. The identification of the apoproteins in the electropherograms is the first step in developing a CE-based quantitation method for measuring serum levels of these apoproteins and their distribution between the lipoprotein fractions. The assay described in this paper is being used as a level 2 and 3 cardiac risk profile analysis for individuals with normal lipid profiles who have a documented or family history of cardiovascular disease.
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PMID:Development of a lipoprotein profile using capillary electrophoresis and mass spectrometry. 937 72

Patients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition.
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PMID:Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study. 992 Jan

Familial hypercholesterolemia is characterized by a high plasma LDL-cholesterol level. The low-density particles are the end-product of the triglyceride-rich particles, i.e. VLDL, synthetized by the liver. These triglyceride-rich particles are subsequently transformed into intermediate density lipoprotein by the lipoprotein lipase and LDL after further triglyceride hydrolysis by the hepatic lipase. The LDL particles are taken up in all cells by the mean of the LDL receptor. A large body of evidence (including experimental, clinical, epidemiological data as well as the results of large trial with lipid lowering drugs) has accumulated to establish that these particles are one of the major causative factor of atherosclerosis and its complications. Two different mechanisms may be at work in the familial hypercholesterolemia: a mutation in the LDL receptor or a single mutation in the apolipoprotein B100. Specific therapeutic intervention should be undertaken to decrease the risk to develop cardiovascular disease, mainly coronary heart disease. The therapeutic intervention includes both a diet low in saturated fatty acids and cholesterol and statins which are now the first line therapy. Fibrates are proposed to those who do not tolerate statins and LDL-apheresis is associated to statin in the rare homozygous familial hypercholesterolemia.
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PMID:[Familial hypercholesterolemia]. 1068 42

Abnormal postprandial lipoproteins are associated with an increased risk for cardiovascular disease. Postprandial remnant lipoproteins were usually analyzed indirectly using retinyl esters (RE) as a chylomicron core label during an oral fat loading test. Apo B-100 containing VLDL remnants in addition to apo B-48 containing chylomicron remnants can also be directly quantified using the RLP-Cholesterol Immunoseparation Assay. This recently available method uses monoclonal antibodies to apo A-I and apo B-100 to remove non-remnant lipoproteins and quantifies cholesterol in the remaining apo E-rich remnant fraction. In the present study we compared the analysis of retinyl ester with the immuno-based RLP-Cholesterol (RLP-C) analysis in measuring postprandial remnant lipoproteins in healthy normolipidemic subjects. Sixteen healthy normolipidemic subjects were selected for this study. Postprandial plasma retinyl esters peaked at 5.0+/-1.2 h, whereas plasma RLP-C showed a peak significantly earlier (P<0.001) at 3.5+/-0.6 h. In comparison, postprandial plasma TG and FFA peaked at 3.3+/-1.1 h (P<0.005 compared to retinyl esters). In conclusion, levels of RLP-C changed, during the postprandial phase, in parallel with plasma TG and FFA concentrations and peaked significantly earlier than retinyl esters. Postprandial measurements of RLP-C can be considered as a fast alternative method for the more laborious retinyl-ester analysis in clinical studies.
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PMID:Isolation of remnant particles by immunoseparation: a new approach for investigation of postprandial lipoprotein metabolism in normolipidemic subjects. 1142 14

Lipoprotein(a) is a cholesterol-enriched lipoprotein, consisting of a covalent linkage joining the unique and highly polymorphic apolipoprotein(a) to apolipoprotein B100, the main protein moiety of low-density lipoproteins. Although the concentration of lipoprotein(a) in humans is mostly genetically determined, acquired disorders might influence synthesis and catabolism of the particle. Raised concentration of lipoprotein(a) has been acknowledged as a leading inherited risk factor for both premature and advanced atherosclerosis at different vascular sites. The strong structural homologies with plasminogen and low-density lipoproteins suggest that lipoprotein(a) might represent the ideal bridge between the fields of atherosclerosis and thrombosis in the pathogenesis of vascular occlusive disorders. Unfortunately, the exact mechanisms by which lipoprotein(a) promotes, accelerates, and complicates atherosclerosis are only partially understood. In some clinical settings, such as in patients at exceptionally low risk for cardiovascular disease, the potential regenerative and antineoplastic properties of lipoprotein(a) might paradoxically counterbalance its athero-thrombogenicity, as attested by the compatibility between raised plasma lipoprotein(a) levels and longevity.
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PMID:Lipoprotein(a): an emerging cardiovascular risk factor. 1262 47

Atherosclerosis is a major complication of diabetes, yet the reason for this remains obscure. Mechanisms of plaque formation are discussed and, in particular, metabolic alterations in the postprandial phase in diabetes are examined. A major metabolic effect of insulin deficiency is a failure to suppress non-esterified fatty acids. The importance of non-esterified fatty acids in the formation of the lipoproteins is discussed, as well as the effects of non-esterified fatty acids on insulin secretion and glucose transport, since the hallmark of Type II diabetes is insulin resistance. The genesis of large triacylglycerol-rich lipoproteins is examined and, in particular, the formation of the intestinally derived chylomicron particle is discussed in some depth with reference to microsomal triacylglycerol transfer protein and apolipoprotein B48, the structural protein for the intestinally derived lipoproteins. The role of microsomal triacylglycerol transfer protein polymorphisms is mentioned. The final section of this review examines alterations to the low-density lipoprotein particle that are found in patients with diabetes and the mechanisms that create an atherogenic low-density lipoprotein particle in diabetes. In conclusion, the lipoprotein cascade is severely disrupted in diabetes, with a major abnormality being found in the metabolism of non-esterified fatty acids. It appears that, at each level of disruption of the normal pathway, the alterations that have been described have the potential to accelerate cholesterol deposition in the plaque and to cause plaque disruption, explaining in part the increased cardiovascular disease found in diabetes.
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PMID:The extended postprandial phase in diabetes. 1450 85

High levels of plasma apolipoprotein B-100 (apoB-100), the principal apolipoprotein of LDL, are associated with cardiovascular disease. We hypothesized that suppression of apoB-100 mRNA by an antisense oligonucleotide (ASO) would reduce LDL cholesterol (LDL-C). Because most of the plasma apoB is made in the liver, and antisense drugs distribute to that organ, we tested the effects of a mouse-specific apoB-100 ASO in several mouse models of hyperlipidemia, including C57BL/6 mice fed a high-fat diet, Apoe-deficient mice, and Ldlr-deficient mice. The lead apoB-100 antisense compound, ISIS 147764, reduced apoB-100 mRNA levels in the liver and serum apoB-100 levels in a dose- and time-dependent manner. Consistent with those findings, total cholesterol and LDL-C decreased by 25-55% and 40-88%, respectively. Unlike small-molecule inhibitors of microsomal triglyceride transfer protein, ISIS 147764 did not produce hepatic or intestinal steatosis and did not affect dietary fat absorption or elevate plasma transaminase levels. These findings, as well as those derived from interim phase I data with a human apoB-100 antisense drug, suggest that antisense inhibition of this target may be a safe and effective approach for the treatment of humans with hyperlipidemia.
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PMID:An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. 1571 85


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