Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The National Cholesterol Education Program (NCEP) has recommended that dietary total fat, saturated fat, and cholesterol intake be reduced to < or = 30% of calories, < 10% of calories, and < 300 mg/day, respectively (Step 1 diet) in the general population to reduce plasma low density lipoprotein (LDL) cholesterol levels and heart disease risk. We examined the LDL cholesterol-lowering response to such a diet (26% fat, 8% saturated fat, and 201 mg/day of cholesterol) as compared to an average American diet (39% fat, 15% saturated fat, and 435 mg/day of cholesterol) in 128 subjects using diet periods of 4-24 weeks for each diet phase. The mean LDL cholesterol reduction was 15% in males (n = 83) and 8% in post-menopausal females (n = 45). The effect of apolipoprotein (apo) E phenotype on responsiveness was examined. LDL cholesterol lowering in males was 14% for 60 apoE3/3 subjects, 23% for 10 apoE3/4 subjects, and 16% for 13 apoE3/2 subjects. Male apoE3/4 subjects had a significantly greater LDL cholesterol reduction (P = 0.006) and a greater decrease in the LDL/HDL ratio (P = 0.047) than apoE3/3 subjects. In females, 7% lowering in LDL cholesterol was observed in 34 apoE3/3 subjects and 11% lowering was observed in 7 apoE3/4 subjects (P = 0.12). A meta-analysis of data from published studies supports this conclusion. These data indicate that apoE phenotype modulates the LDL cholesterol-lowering response to a diet meeting NCEP Step 1 criteria, and that male subjects carrying the apoE4 allele are more responsive than other subjects.
 ...
PMID:Effect of apolipoprotein E phenotype on diet-induced lowering of plasma low density lipoprotein cholesterol. 786 75

After heart disease, cancer and stroke, Alzheimer's disease (AD) is the fourth major cause of death in the developed countries. Due to demographic changes, this situation will further worsen in the future. With the use of molecular biology techniques, important progress has recently been made in the understanding of the molecular changes leading to some forms of this disabling illness. The first step was the partial sequencing of the amyloid protein accumulating in the senile plaques and vascular deposits characteristic of AD. This allowed the cloning of a cDNA coding for a long amyloid precursor protein (APP). During the last few years, independent reports have described the presence of several reproducible point mutations in specific codons of APP in early onset familial Alzheimer patients. These mutations are responsible for an abnormal processing of APP, leading to the formation of pathological beta/A4 amyloid deposits. beta/A4 has been shown to possess neurotrophic properties in embryonic neurones and to be a potent neurotoxic agent in differentiated hippocampal neurones. More recently, modifications of intracellular calcium, activation of kinases, free radical generation and anomalies in potassium channels have been described as possible mechanisms of beta/A4 toxicity. Some forms of Apo-E lipoprotein may be an additional risk factor. Hence, it now seems possible to elaborate a coherent theory to explain the cascade of events leading to the development of AD. Genetically induced point mutations or environmental factors may produce a modification of the APP metabolism and processing. As a consequence, abnormal deposits of beta/A4 are formed. They may exert direct or indirect neurotoxic actions. A degeneration of cholinergic, catecholaminergic and other neurones follows, leading to the well known cognitive and behavioural changes of AD.
 ...
PMID:Towards a pharmacological approach of Alzheimer's disease based on the molecular biology of the amyloid precursor protein (APP). 799 77

For quantitative traits associated with risk to complex diseases, such as heart disease, single major locus models are likely to be too simplistic. Currently, researchers have begun to use oligogenic models of inheritance, but the resolving power of these models remains to be determined. As the major apoprotein of high density lipoprotein (HDL), apolipoprotein A1 (apo-A1) is generally accepted as a protective factor for coronary artery disease. Although familial aggregation of apo-A1 levels has been reported, the mode of inheritance of apo-A1 remains ill defined. In the present study, we conducted a segregation analysis comparing a series of one-locus and two-locus univariate models for apo-A1 levels in a sample of 137 families ascertained through probands undergoing elective, diagnostic coronary angiography. A two-locus Mendelian model fit these data significantly better than any one-locus model. The incorporation of the second major locus into the model of inheritance leads to a significant improvement in the fit, and a significant decrease of the residual heritability. The best-fitting model included two loci with a reciprocal pattern of epistasis generating 4 distinct genotypic distributions. Taken together, these two major loci account for 58% of the variance of adjusted apo-A1 levels. This demonstration of a second major locus controlling apo-A1 levels may explain the equivocal results obtained from previous studies. This two-locus model may be more powerful for linkage analysis to map one or both of these quantitative trait loci.
 ...
PMID:Segregation analysis of two-locus models regulating apolipoprotein-A1 levels. 952 12

Platelets are small cells, 1/14th the volume of erythrocytes, and about 1000 billion circulate in human blood as smooth anucleate disks. Their job is to survey the lining of our blood vessels, the endothelium. In acute damage and extravasation, platelets are activated by contact with exposed collagen and aggregate together at the wound sites to initiate clotting and stop bleeding. Forming a physical plug to seal a hemorrhaging vessel is the key role of blood platelets. However, milder injury to the endothelium, perhaps a result of high blood pressure, raised plasma cholesterol, or smoking, also causes platelets to adhere to the internal walls of arteries. Such precipitate adhesion and activation of platelets initiates an inflammatory response of the vessel wall and predisposes to vascular complications, including thrombosis, premature heart disease, myocardial infarcts or strokes, and diabetes. It is essential, therefore, that during normal vascular hemostasis platelet activation is tightly controlled. Indeed, both platelets and endothelial cells produce and secrete chemicals that directly inhibit platelet aggregation. A key agent is the free radical gas nitric oxide (NO). Here, we review how this 30-Da molecular messenger is synthesized by a catalytic cassette 10,000 times larger and how it functions to suppress platelet "stickiness." We also present new evidence that directly links plasma lipoproteins with platelet activation: we describe at the molecular level how apoE, a protein with a prominent role in cholesterol transport, interacts with the platelet surface to stimulate NO production and hence attenuate platelet activation.
 ...
PMID:Nitric oxide and platelet aggregation. 1023 45

Apolipoprotein (apo) E plays an important role in lipid metabolism, and the major isoforms of apoE (apoE2, apoE3, and apoE4) have significantly different metabolic effects. Apolipoprotein E4 is associated with a higher risk of both heart disease and Alzheimer's disease (AD). Patients homozygous for apolipoprotein E2 are predisposed to type III hyperlipoproteinemia, and apoE2 may be protective against AD. Structure/function studies have proved to be a useful tool in understanding how the different apoE isoforms result in different pathological consequences. As these studies continue, it is essential to have a reliable method to produce large quantities of apoE and mutants of apoE. We describe here a method of apoE production in Escherichia coli strain BL21(DE3). The cDNA from apoE isoforms was inserted into a pET32a vector with a T7 promoter and a fusion partner (thioredoxin). The T7 promoter results in high expression of an easily purified His-tagged fusion protein. A thrombin recognition site was positioned in the expression vector so that only two novel amino acids (Gly-Ser) are added to the amino terminus of apoE following the removal of thioredoxin. Approximately 20 mg of apoE is obtained from a 1-liter culture. The major isoforms of apoE produced with this system were extensively characterized for their ability to bind the low-density lipoprotein (LDL) receptor, for their characteristic lipid association preferences, and for their stability as measured by guanidine denaturation. The recombinant proteins behaved identically to plasma-derived apoE isoforms.
 ...
PMID:Functional characterization of apolipoprotein E isoforms overexpressed in Escherichia coli. 1041 18

Elevated plasma Lp(a) is an independent risk factor for cardiovascular disease. Unique to Lp(a) is the apoprotein, apo(a) which can vary from 250 to 800 kDa in molecular weight. Small isoforms are also associated with the risk of cardiovascular disease. The purpose of this study was to examine the association of Lp(a) concentration, apo(a) size, and Lp(a) lysine-binding site(s) (LBS) function in patients with early onset heart disease, and age-matched controls. Mean values of Lp(a) were significantly higher in the patients than for the age-matched group. The smallest molecular weight isoform for each subject had significantly fewer kringles for the patients than the age-matched controls. There was a significant correlation between LBS activity and kringle number in the single-banded phenotypes of the patients, but not the controls. LBS activity was significantly higher in patients with small isoforms (< or =18 kringles) compared to controls. The odds ratio for coronary artery disease for high LBS activity and high Lp(a) concentration was 4.4 (p = 0.002) and for high LBS activity and small isoforms was 10.1 (p = 0.002). In the patients, Lp(a) concentration was higher, apo(a) size was smaller, and LBS activity higher in the small isoforms compared to the controls. This study suggests an association of high LBS activity in small isoforms of Lp(a) with disease in humans.
 ...
PMID:Impact of apolipoprotein(a) isoform size heterogeneity on the lysine binding function of lipoprotein(a) in early onset coronary artery disease. 1130 6

Human apolipoprotein (apo) E exists as one of three major isoforms, E2, E3 or E4. Individuals carrying the epsilon 4 allele have an increased risk of heart disease and premature onset of Alzheimer's disease. To investigate the molecular basis for this phenomenon, the N-terminal domain of apoE3, apoE2 and apoE4 were expressed in bacteria, isolated and employed in lipid binding and stability studies. Far UV circular dichroism spectroscopy in buffer at pH 7 revealed a similar amount of alpha-helix secondary structure for the three isoforms. By contrast, differences were noted in apoE-NT isoform-specific transformation of bilayer vesicles of dimyristoylphosphatidylglycerol (DMPG) into discoidal complexes. ApoE4-NT induced transformation was most rapid, followed by apoE3-NT and apoE2-NT. To determine if differences in the rate of apoE-NT induced DMPG vesicle transformation is due to isoform-specific differences in helix bundle stability, guanidine HCl denaturation studies were conducted. The results revealed that apoE2-NT was the most stable, followed by apoE3-NT and apoE4-NT, establishing an inverse correlation between helix bundle stability and DMPG vesicle transformation rate at pH 7. When the zwitterionic dimyristoylphosphatidylcholine (DMPC) was employed as the model lipid surface, interaction of apoE-NT isoforms with the lipid substrate was slow. However, upon lowering the pH from 7 to 3, a dramatic increase in the rate of DMPC vesicle transformation rate was observed for each isoform. To evaluate if the increased DMPC vesicle transformation rates observed at low pH is due to pH-dependent alterations in helix bundle stability, guanidine HCl denaturation studies were performed. ApoE2-NT and apoE3-NT displayed increased resistance to denaturation as a function of decreasing pH, while apoE4-NT showed no change in stability. Studies with the fluorescent probe, 8-anilino-1-naphthalene sulfonic acid, indicated an increase in apoE hydrophobic surface exposure upon decreasing the pH to 3.0. Taken together, the data indicate that changes in the stability of secondary structure elements in apoE-NT isoforms are not responsible for pH-induced increases in lipid binding activity. It is likely that pH-induced disruption of inter-helical tertiary contacts may promote helix bundle conformational changes that present the hydrophobic interior of the protein to potential lipid surface binding sites.
 ...
PMID:Lipid binding ability of human apolipoprotein E N-terminal domain isoforms: correlation with protein stability? 1264 85

Atherosclerosis is a primary cause of heart disease and stroke; it is the underlying cause of about 50% of all deaths in Western countries. It is known that early detection of atherosclerotic lesions would significantly reduce the risk of mortality. The objective of this study was to develop a radioimaging method for early detection of atherosclerotic plaques. A novel polyiodinated cholesterol analog, cholesteryl 1,3-diiopanoate glyceryl ether (C2I, patent pending), was synthesized and radiolabeled with 125I. 125I-C2I was incorporated into acetylated low-density lipoprotein (AcLDL), which is considered to be an atherosclerotic plaque-seeking carrier. 125I-C2I was also prepared as a chylomicron-like emulsion. Transgenic mice deficient in apoE and low-density lipoprotein receptors (LDLR), known as apoE/LDLR double knockout, were used as an animal model of early atherosclerosis. 125I-C2I/AcLDL or 125I-C2I emulsion was injected into the apoE/LDLR knockout mice via the tail vein, and the mice were killed humanely 24 h after injection. Various tissues including aorta were removed and radioactivity was determined. The aorta samples were also imaged to determine the accumulation of radioactivity from C2I. The images were compared to the atherosclerotic lesions revealed by histological studies. It was found that both 125I-C2I/AcLDL and 125I-C2I emulsion resulted in accumulation of radioactivity at the site of early atherosclerotic lesions, and they therefore may be useful for early detection of atherosclerosis.
 ...
PMID:Ex vivo evaluation of a novel polyiodinated compound for early detection of atherosclerosis. 1297 7

Apolipoprotein (apo) E4 is a risk factor for heart disease, Alzheimer's disease, and other forms of neurodegeneration, but the underlying mechanisms are unknown. Domain interaction, a structural property that distinguishes apoE4 from apoE2 and apoE3, results in more rapid turnover and lower plasma levels of apoE4. To determine whether domain interaction affects brain apoE levels, we analyzed brain homogenates from human apoE3 and apoE4 knock-in mice, wild-type mice, and Arg-61 apoE mice, in which domain interaction was introduced by gene targeting. As determined on Western blots, the hemibrain, cortex, hippocampus, and cerebellum of knock-in mice had 30-40% lower levels of apoE4 than apoE3, and Arg-61 mice had 25-50% lower apoE levels than wild-type mice. In the CSF, Arg-61 apoE level was 40% lower than the wild-type level. Arg-61 apoE mRNA levels were similar to or slightly higher than wild-type apoE mRNA levels. Thus, the lower Arg-61 apoE levels were not attributable to decreased mRNA levels. In culture medium from heterozygous Arg-61/wild-type and apoE4/apoE3 primary astrocytes, Arg-61 apoE and apoE4 levels were lower than wild-type apoE and apoE3, respectively, suggesting that primary astrocytes secrete lower amounts of Arg-61 apoE and apoE4. These results demonstrate that domain interaction is responsible for the lower levels of both human apoE4 and mouse Arg-61 apoE in mouse brain. Cells may recognize apoE4 and Arg-61 apoE as misfolded proteins and target them for degradation or accumulation. Thus, degradation/accumulation or lower levels of apoE4 may contribute to the association of apoE4 with Alzheimer's disease.
 ...
PMID:Effect of domain interaction on apolipoprotein E levels in mouse brain. 1629 38

Disease-associated amyloid deposits contain both fibrillar and nonfibrillar components. The majority of these amyloid components originate or coexist in the bloodstream. To understand the nature of the interaction between the nonfibrillar and fibrillar components, we have developed a centrifugation method to isolate fibril binding proteins from human serum. Amyloid fibrils composed of either Abeta peptide or apolipoprotein C-II (apoC-II) cosedimented with specific serum proteins. Gel electrophoresis, mass spectrometry peptide fingerprinting, and Western analysis identified the major binding species as proteins found in HDL particles, including apoA-I, apoA-II, apoE, clusterin, and serum amyloid A. Sedimentation analysis showed that purified human HDL and recombinant apoA-I lipid particles bound directly to Abeta and apoC-II amyloid fibrils. These studies reveal a novel function of HDL that may contribute to the well-established protective effect of this lipoprotein class in heart disease.
 ...
PMID:High density lipoproteins bind Abeta and apolipoprotein C-II amyloid fibrils. 1643 77


1 2 Next >>