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)

Mutations in the low density lipoprotein (LDL)-receptor gene cause familial hypercholesterolemia (FH), an autosomal dominant disease associated to an increased risk of premature atherosclerosis. We describe two novel mutations found in Italian families and consisting in minor gene rearrangements. The first one (FH-Pisa) is a tetranucleotide insertion occurring in exon 8, which causes a frameshift and a premature stop codon. The second one (FH-Chieti3) occurs at the 3'-end of exon 4 and consists in a trinucleotide deletion replaced by a six-base insertion, so that the reading frame is maintained with a glutamic acid-to-cysteine substitution at codon 207 and the insertion of a lysine at codon 208. Both mutations occur in regions of the LDL-receptor gene which can be considered hotspots for minor rearrangements.
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PMID:Two novel mutations consisting in minor gene rearrangements in the human low density lipoprotein receptor gene in Italian patients affected by familial hypercholesterolemia. Mutations in brief no. 194. Online. 1066 Mar 40

Hyperhomocysteinemia is an independent risk factor for atherosclerosis and vascular occlusive diseases. Measurements of total homocysteine (Hcy) require an accurate reproducible method. A high-performance liquid chromatographic (HPCL) method for evaluating plasma Hcy after reduction with 2-mercaptoethanol and precolumn derivatization with iodoacetic acid and o-phthaldialdehyde is described. The resultant derivatives were separated on reverse-phase column C18 in the isocratic HPCL mode with fluorimetric detection. The detection limit for Hcy is 0.8 mumol/liter. The concentration of Hcy after overnight fasting was increased significantly (p < 0.02) in the patients in comparison with the control (11.7 +/- 1.1 vs. 8.3 +/- 0.5 mumol/liter). The method can be used for measuring the concentrations of asparaginic acid, glutamic acid, cysteine, asparagine, serine, and glutamine.
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PMID:[Measurement of blood homocysteine by high performance liquid chromatography (HPLC)]. 1150 83

Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expression is implicated in the vascular re-modelling events preceding plaque rupture (the most common cause of acute myocardial infarction). Reduced MMP9 activity, either by genetic manipulation or through pharmacological intervention, has an impact on ventricular re-modelling following infarction. MMP9 activity may therefore represent a key mechanism in the pathogenesis of heart failure. We have determined the crystal structure, at 2.3 A resolution, of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor as well as the complex of the same inhibitor bound to an active-site mutant (E402Q) at 2.1 A resolution. MMP9 adopts the typical MMP fold. The catalytic centre is composed of the active-site zinc ion, co-ordinated by three histidine residues (401, 405 and 411) and the essential glutamic acid residue (402). The main differences between the catalytic domains of various MMPs occur in the S1' subsite or selectivity pocket. The S1' specificity site in MMP9 is perhaps best described as a tunnel leading toward solvent, as in MMP2 and MMP13, as opposed to the smaller pocket found in fibroblast collagenase and matrilysin. The present structure enables us to aid the design of potent and specific inhibitors for this important cardiovascular disease target.
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PMID:Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor. 1205 44

Human cytomegalovirus (HCMV) encodes a G protein-coupled receptor (GPCR), named US28, which shows homology to chemokine receptors and binds several chemokines with high affinity. US28 induces migration of smooth muscle cells, a feature essential for the development of atherosclerosis, and may serve as a co-receptor for human immunodeficiency virus-type 1 entry into cells. Previously, we have shown that HCMV-encoded US28 displays constitutive activity, whereas its mammalian homologs do not. In this study we have identified a small nonpeptidergic molecule (VUF2274) that inhibits US28-mediated phospholipase C activation in transiently transfected COS-7 cells and in HCMV-infected fibroblasts. Moreover, VUF2274 inhibits US28-mediated HIV entry into cells. In addition, VUF2274 fully displaces radiolabeled RANTES (regulated on activation normal T cell expressed and secreted) binding at US28, apparently with a noncompetitive behavior. Different analogues of VUF2274 have been synthesized and pharmacologically characterized, to understand which features are important for its inverse agonistic activity. Finally, by means of mutational analysis of US28, we have identified a glutamic acid in transmembrane 7 (TM 7), which is highly conserved among chemokine receptors, as a critical residue for VUF2274 binding to US28. The identification of a full inverse agonist provides an important tool to investigate the relevance of US28 constitutive activity in viral pathogenesis.
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PMID:Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. 1245 73

Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ABCA1, the defective molecule in Tangier disease, mediates the efflux of phospholipids and cholesterol from cells to apoA-I, reversing foam cell formation. In ABCA1, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhances the degradation of ABCA1 by calpain protease and thereby controls the cell surface concentration and cholesterol efflux activity of ABCA1. In an apparent positive feedback loop, apoA-I binds ABCA1, promotes lipid efflux, inhibits calpain degradation, and leads to increased levels of ABCA1. ApoA-I infusion also increases ABCA1 in vivo. These studies reveal a novel mode of regulation of ABCA1 by PEST sequence-mediated calpain proteolysis that appears to be reversed by apolipoprotein-mediated phospholipid efflux. Inhibition of ABCA1 degradation by calpain could represent a novel therapeutic approach to increasing macrophage cholesterol efflux and decreasing atherosclerosis.
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PMID:A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I. 1251 93

P-selectin plays an important role in the development of various diseases, including atherosclerosis and thrombosis. In our laboratory we recently identified a number of specific human P-selectin-binding peptides containing a Glu-Trp-Val-Asp-Val consensus motif, displaying a low micromolar affinity for P-selectin (IC(50) = 2 microm). In search of more potent antagonists for P-selectin, we have optimized the EWVDV pentapeptide core motif via a two-step combinatorial chemistry approach. A dedicated library of peptide derivatives was generated by introducing seven substituents at the N and C termini of the motif. In particular, pentapeptides with gallic acid or 1,3,5-benzenetricarboxylic acid substituents at the N terminus proved to be considerably more potent inhibitors of P-selectin binding than the parental peptide. After removal of the N-terminal glutamic acid from the core sequence, which appeared to be replaceable by a carboxamide function without loss of affinity, a second library was synthesized to map the chemical moieties within the gallic acid or 1,3,5-benzenetricarboxyl acid groups responsible for the enhanced P-selectin binding. Moreover, by varying the length and rigidity of the connective spacer, we have further optimized the spatial orientation of the N-terminal substituent. The combined use of phage display and subsequent combinatorial chemistry led to the design of a number of gallic acid- containing peptides with low nanomolar affinity for P-selectin both under static and dynamic conditions (IC(50) = 15.4 nm). These small synthetic antagonists, which are equally as potent as the natural ligand P-selectin glycoprotein ligand-1, are promising leads in anti-atherothrombotic therapy.
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PMID:Rational optimization of a short human P-selectin-binding peptide leads to nanomolar affinity antagonists. 1252 1

We report two novel APOB mutations causing short apolipoprotein B (apoB) truncations undetectable in plasma and familial hypobetalipoproteinemia (FHBL). In Family 56, a 5 bp deletion in APOB exon 7 (870_874del5) causes a frame shift, converting tyrosine to a stop codon (Y220X) and producing an apoB-5 truncation. In Family 59, a point mutation (1941G>T) in APOB exon 13 converts glutamic acid to stop codon (E578X), specifying apoB-13. A recurrent mutation in exon 26 (4432delT) produces apoB-30.9 in Family 58. In some members of these families, we observed that plasma low-density lipoprotein (LDL) cholesterol and apoB levels were unusually low even for subjects heterozygous for FHBL. To ascertain whether genetic variations in apolipoprotein E (apoE) would explain some of the variations of apoB and LDL cholesterol levels, apoE genotypes were assessed in affected subjects from a total of eight FHBL families with short apoB truncations. Heterozygous FHBL with the epsilon3/epsilon4 genotype had 10-1 5mg/dL higher plasma LDL cholesterol and apoB levels compared to subjects with the epsilon2/epsilon3 and epsilon3/epsilon3 genotypes. The apoE genotype has been reported to account for approximately 10% of the variation of LDL cholesterol in the general population. It accounted for 15-60% of the variability of plasma LDL cholesterol or apoB levels in our FHBL subjects. The physiologic bases for the greater effects of apoE in FHBL remain to be determined.
Atherosclerosis 2005 Jan
PMID:Genetic variants of ApoE account for variability of plasma low-density lipoprotein and apolipoprotein B levels in FHBL. 1558 7

Short peptides resembling the Helicobacter pylori urease antigen (UreB F8 Ser-Ile-Lys-Glu-Asp-Val-Gln-Phe) with deleted aspartic acid and glutamic acid residues, anchored through a triazine linker via the N-terminal moiety to cellulose plate were prepared. The peptides were used for binding of antibodies from sera of patients with medically confirmed atherosclerosis. Recognition of the peptides was also tested with anti-Jack beans urease antibodies. The important role of a Gly-Gly spacer separating the peptides from the cellulose support was shown. Different patterns of binding of antibodies from H. pylori infected patients and anti-Jack bean urease antibodies were observed only in the case of pentapeptides. The peptide Gly-Gly-Leu-Val-Phe-Lys-Thr was recognized by most of the tested sera.
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PMID:Synthetic peptides mimicking antigenic epitope of Helicobacter pylori urease. 1649 40

Vitamin K is a nutrient that was originally identified as an essential factor for blood coagulation. Recently, vitamin K has emerged as a potential protector against osteoporosis, atherosclerosis, and hepatocarcinoma. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone and possibly in vasculature, exists widely in the otherwise healthy adult population. Vitamins K1 and K2 have been shown to exert protective effects against osteoporosis, although it is important that the beneficial effects will be further confirmed by large-scale, randomized, clinical trials. Increasing evidence implicates a role for vitamin K in calcification of arteries and atherogenesis. Moreover, the therapeutic potential of vitamin K2 as an antihepatoma drug has recently been highlighted. Most of the new biological functions of vitamin K in bone, vasculature, and hepatoma cells are considered attributable to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by vitamins K1 and K2. In contrast, vitamin K2-specific, gamma-carboxylation-unrelated functions have also been demonstrated. Thus, biological differences between vitamins K1 and K2 and potential involvement of gamma-carboxylation-independent actions in the new roles of vitamin K remain open issues. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in human health deserve further investigations.
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PMID:Pleiotropic actions of vitamin K: protector of bone health and beyond? 1681 98

Macrophages play an important role in inflammatory processes and are crucially involved in the onset and progression of atherosclerosis and tumorigenesis. Therefore, macrophages are regarded as an excellent target for therapeutic intervention. Since the scavenger receptor class A (SRA) is highly expressed on macrophages, we developed in the present study an SRA-specific particulate drug carrier by providing phosphatidylcholine liposomes with a targeting ligand for SRA. To enable firm association with liposomes, the high-affinity SRA ligand decadeoxyguanine was covalently attached via a linker to lithocholic oleate (LCO-dA(2)dG(10)). Incorporation of LCO-dA(10)dG(2) into liposomes resulted in an increased electronegative surface charge and a dramatically enhanced serum clearance (t(1/2) < 2 min versus > 5 h). The LCO-dA(2)dG(10)-induced liposome clearance was fully dependent on SRA, as the clearance could be efficiently inhibited by the SRA competitor polyinosinic acid. LCO-dA(2)dG(10) enhanced the affinity of liposomes for SRA in vivo selectively, since introduction of overall or clustered negative charges by other modifications (e.g. oxidation, inclusion of phosphatidylserine, or exposure of glutamic acid residues) did not affect their serum clearance substantially, albeit that these modifications resulted in an at least equally high negative surface charge. LCO-dA(2)dG(10) also increased the association of liposomes with RAW264.7 cells, resulting in an enhanced intracellular delivery and bioactivity of encapsulated dexamethasone-phosphate. Therefore, the SRA-specificity of LCO-dA(2)dG(10)-liposomes may be applied for the specific delivery of drugs to macrophages, which may be of therapeutic benefit in general inflammatory disorders, atherosclerosis, and tumorigenesis.
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PMID:Selective targeting of liposomes to macrophages using a ligand with high affinity for the macrophage scavenger receptor class A. 1692 21


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