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)

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been inconsistently associated with hypertension. This inconsistency may derive from population stratification secondary to ethnic diversity, and consideration limited to only one rather than combinations of polymorphisms. We studied three genetic variations in the eNOS gene: a single nucleotide polymorphism in the promoter region (T-786C), in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a) of the eNOS gene in hypertensives (112 whites and 91 blacks) and normotensives (113 whites and 87 blacks). In addition, we also examined the association of eNOS gene haplotypes with hypertension in white and black subjects. No differences were observed in the frequencies of genotypes and alleles of the three polymorphisms when white hypertensives and white normotensives were compared, or when black hypertensives and black normotensives were compared (all P>0.05). Conversely, the haplotypes "T Asp b" and "C Glu b" were more common among white (16 and 24%, respectively) and black (17 and 16%, respectively) normotensives than in white (7 and 8%, respectively) and black (4 and 6%, respectively) hypertensives, respectively (all P<0.0039). In addition, the haplotype "C Asp b" was more commonly found in white hypertensives than in white normotensives (P=0.0007). These results suggest a contribution of eNOS haplotypes to the development of hypertension that is obscured when specific eNOS genotypes alone are considered. In addition, our results suggest two eNOS haplotypes associated with a protective effect against hypertension in both ethnic groups, and one eNOS haplotype conferring susceptibility to hypertension in white subjects.
Atherosclerosis 2006 Jun
PMID:Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. 1616 96

Type 2 diabetes mellitus (T2DM) and hypertension (HT) commonly coexist. While endothelial nitric oxide synthase (eNOS) haplotypes have been associated with HT, it is unknown whether eNOS genotypes/haplotypes are associated with altered susceptibility to HT in patients with T2DM. We studied the distribution of three eNOS genetic polymorphisms: a single nucleotide polymorphism in the promoter region (T(-786)C), in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4(b/a). Genotypes were determined for 102 healthy controls, 119 patients with HT, 66 patients with T2DM, and 113 patients with T2DM+HT. In addition, we also compared the distribution of eNOS haplotypes in the four groups of subjects. No differences were found in genotype and allele distribution among the four groups. Conversely, the haplotypes "C Glu b" and "C Asp b" were, respectively, more and less common in healthy controls than in HT or in T2DM+HT groups (24% versus 6% and 5%, respectively; both P<0.00625; and 8% versus 18% and 18%, respectively; both P<0.00625). Moreover, DM patients presented an overall distribution of eNOS haplotypes that was not different from healthy controls (P>0.05). Additionally, the haplotypes "C Glu b" and "C Asp b" were, respectively, more and less common in T2DM group than in T2DM+HT group (19% versus 5%; and 7% versus 18%, respectively; both P<0.00625). Our findings suggest a protective effect for eNOS haplotype "C Glu b" against the development of hypertension, and that haplotype "C Asp b" increases the susceptibility to hypertension in patients without or with T2DM.
Atherosclerosis 2006 Nov
PMID:Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. 1642 44

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

Oxidatively modified low-density lipoprotein (OxLDL) is present in atherosclerotic lesions and has been proposed to play an important role in atherogenesis. Asp-hemolysin, a hemolytic toxin from Aspergillus fumigatus, is a binding protein for OxLDL. This study was undertaken to clarify the biological activity of OxLDL and the potentially of Asp-hemolysin as a regulation factor to atherogenic effect by OxLDL. We first analyzed the interaction between OxLDL and blood coagulation factors, which are involved in the blood coagulation pathway. OxLDL caused prolongation of activated partial thromboplastin time (APTT) as a parameter of the intrinsic pathway of blood coagulation in a dose- and oxidation time-dependent manner. In addition, OxLDL significantly inhibited blood coagulation factor VIII, IX, and XI activity. Furthermore, we demonstrated that factor VIII binds to OxLDL. These results indicate that the binding of factor VIII to OxLDL affects the intrinsic pathway of the blood coagulation cascade. Next, to clarify the structure-function relationship of Asp-hemolysin, we expressed Asp-hemolysin in Escherichia coli as a fusion protein with a maltose-binding protein (MBP) and purified it by affinity chromatography. The purified recombinant Asp-hemolysin showed an immunoreactivity with the anti-Asp-hemolysin antibody. In addition, MBP-Asp-hemolysin fusion protein exhibited binding activity to Ox-LDL as did native Asp-hemolysin. Furthermore, to investigate the effect of the Asp-hemolysin-related peptide (P-21), a synthetic peptide derived from a region of Asp-hemolysin that is rich in positive charges, on macrophage proliferation induced by OxLDL. P-21 inhibited OxLDL-induced macrophage proliferation in a dose-dependent manner. In addition, the binding analysis of P-21 to OxLDL indicated that P-21 binds to OxLDL. These results indicate that P-21 inhibits the OxLDL-induced macrophage proliferation through binding of P-21 to OxLDL. In conclusion, we have shown that OxLDL affects the intrinsic pathway of blood coagulation, and its mechanism is dependent on the binding of factor VIII to OxLDL. Furthermore, we indicate the possibility that Asp-hemolysin is a useful tool to investigate the pathophysiological significance of OxLDL. In particular, since the P-21, an Asp-hemolysin-related peptide, inhibits the OxLDL-induced macrophage proliferation through binding of P-21 to OxLDL, further study on the binding mechanism between Asp-hemolysin-related peptide and OxLDL may provide important information on the prevention and treatment of atherosclerosis.
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PMID:[Biological activity of Asp-hemolysin as a regulation factor to atherogenic effect by oxidized low-density lipoprotein]. 1701 24

Osteopontin, also called cytokine Eta-1, is a multifunctional protein containing Arg-Gly-Asp-Ser (RGDS) cell-binding sequence. It interacts with alpha(v)beta1, alpha(v)beta3 and alpha(v)beta5 integrins and CD44 receptors. OPN is suggested to play a role during inflammation via the recruitment and retention of macrophages and T-cells to inflamed sites. OPN regulates the production of inflammatory cytokines and nitric oxide in macrophages. In this review, we will discuss diverse roles of OPN related to cardiovascular diseases, including atherosclerosis, valvular stenosis, hypertrophy, myocardial infarction and heart failure.
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PMID:Osteopontin: a novel inflammatory mediator of cardiovascular disease. 1712 94

Leukotriene B(4) (LTB(4)) mediates a variety of inflammatory diseases such as asthma, arthritis, atherosclerosis, and cancer through activation of the G-protein-coupled receptor, BLT1. Using in silico molecular dynamics simulations combined with site-directed mutagenesis we characterized the ligand binding site and activation mechanism for BLT1. Mutation of residues predicted as potential ligand contact points in transmembrane domains (TMs) III (H94A and Y102A), V (E185A), and VI (N241A) resulted in reduced binding affinity. Analysis of arginines in extracellular loop 2 revealed that mutating arginine 156 but not arginine 171 or 178 to alanine resulted in complete loss of LTB(4) binding to BLT1. Structural models for the ligand-free and ligand-bound states of BLT1 revealed an activation core formed around Asp-64, displaying multiple dynamic interactions with Asn-36, Ser-100, and Asn-281 and a triad of serines, Ser-276, Ser-277, and Ser-278. Mutagenesis of many of these residues in BLT1 resulted in loss of signaling capacity while retaining normal LTB(4) binding function. Thus, polar residues within TMs III, V, and VI and extracellular loop 2 are critical for ligand binding, whereas polar residues in TMs II, III, and VII play a central role in transducing the ligand-induced conformational change to activation. The delineation of a validated binding site and activation mechanism should facilitate structure-based design of inhibitors targeting BLT1.
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PMID:Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1. 1723 98

Inducing expression of the cholesterol-catabolizing enzyme cholesterol 7alpha-hydroxylase (CYP7A1) in the liver can be an effective strategy in preventing hypercholesterolemia and atherosclerosis. We used HepG2 cells to investigate the effects of 1 mM dipeptides having a C-terminal lysine group on the CYP7A1 mRNA level. We found that the dipeptides Asp-Lys, Glu-Lys, and Trp-Lys significantly increased the CYP7A1 mRNA level.
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PMID:Effects of dipeptides having a C-terminal lysine on the cholesterol 7alpha-hydroxylase mRNA level in HepG2 cells. 1734 15

The extracellular matrix protein osteopontin (OPN) plays a nonredundant role in atherosclerosis and restenosis. Here we investigated the impact of OPN up-regulation in an in vitro model of re-endothelialization after mechanical injury of the endothelial cell monolayer. Murine aortic endothelial (MAE) cells interact via alpha(v) integrins with the integrin-binding Arg-Gly-Asp OPN sequence and adhere to immobilized OPN. On this basis, MAE cells were stably transfected with a wild-type OPN cDNA (OPN-MAE cells), with an OPN mutant lacking the Arg-Gly-Asp sequence (DeltaRGD-OPN-MAE cells), or with vector alone (mock-MAE cells). When compared with mock-MAE and DeltaRGD-OPN-MAE cells, OPN-MAE cells showed a reduced sprouting activity in fibrin gel, a reduced motility in a Boyden chamber assay, and a reduced capacity to repair the wounded monolayer. Accordingly, OPN-MAE cells at the edge of the wound were unable to form membrane ruffles, to reorganize their cytoskeleton, and to activate the focal adhesion kinase and the small GTPase Rac1, key regulators of the cell entry into the first phase of the cell migration cycle. Accordingly, wounded OPN-MAE cells failed to activate the intracellular signals RhoA and ERK1/2, involved in the later phases of the cell migration cycle. Also, parental MAE cells showed reduced re-endothelialization after wounding when seeded on immobilized OPN and exhibited increased adhesiveness to OPN-enriched extracellular matrix. In conclusion, OPN up-regulation impairs re-endothelialization by inhibiting the first phase of the cell migration cycle via alpha(v) integrin engagement by the extracellular matrix-immobilized protein. This may contribute to the adverse effects exerted by OPN in restenosis and atherosclerosis.
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PMID:Osteopontin overexpression inhibits in vitro re-endothelialization via integrin engagement. 1745 74

We previously identified a G>A single nucleotide polymorphism (SNP) between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains at position 2077 in the coding region of Vcam1 that leads to substitution of an amino acid from aspartic acid (D) to asparagine (N) in the protein product. In the present study, we investigated the association of this SNP with atherosclerosis susceptibility using a panel of inbred mouse strains, a set of recombinant inbred (RI) strains derived from B6 and C3H mice, and a cohort of F2 mice derived from B6 and C3H apolipoprotein E-deficient (apoE(-/-)) mice. Inbred strain analysis revealed that mouse strains with the B6 Vcam1 genotype developed significantly larger atherosclerotic lesions than strains with the C3H genotype (4622+/-2816 microm(2)/section versus 362+/-697 microm(2)/section; P=0.029). BXH RI strains with the B6 Vcam1 genotype also developed larger atherosclerotic lesions than those with the C3H genotype (8305+/-9031 microm(2)/section versus 2139+/-2931 microm(2)/section) although the difference was not statistically significant (P=0.13). In contrast, no association was detected between Vcam1 and atherosclerotic lesion size in F2 mice. The present data indicate that the G>A mutation of Vcam1 is associated with atherosclerotic lesion formation in the dietary but not apoE(-/-) models of atherosclerosis and this association suggests a role for the Vcam1 gene in influencing atherosclerosis susceptibility.
Atherosclerosis 2008 Jan
PMID:Association of a Vcam1 mutation with atherosclerosis susceptibility in diet-induced models of atherosclerosis. 1757 30

The paleopathological study of 31 Italian Renaissance mummies from the Basilica of S. Domenico Maggiore in Naples has allowed us to perform about 20 diagnoses, of which 5 concern infectious (smallpox, hepatitis, condyloma, syphilis and pneumonia), 3 metabolic (obesity, atherosclerosis, gallstones), I articular (DISH) and 2 neoplastic (colon adenocarcinoma and skin carcinoma) diseases. The mummy of an anonymous child, dated back to the 16th century (14C: 1569 +/- 60), presented a diffuse vesiculopustular exanthema. Macroscopic aspects and regional distribution suggested smallpox, while EM revealed many egg-shaped, virus-like particles (250 x 50 nm), with a central dense core. Following incubation with anti-smallpox virus antiserum and protein A-gold complex immunostaining, the particles resulted completely covered with protein A-gold. These results clearly show that this Neapolitan child died of a severe form of smallpox some four centuries ago. The mummy of Maria d'Aragona, Marquise of Vasto (1503-1568), revealed on the left arm an oval, cutaneous ulcer (15 x l0 mm) with linen dressing. Indirect immunofluorescence with anti-treponema pallidum antibody identified a large number of filaments with the morphological characteristics of fluorescent treponemes. Electron microscopy evidenced typical spirochetes, with axial fibril. These findings clearly demonstrate a treponemal, probably venereal, infection. Further examination of the mummy showed a large peduncolate arborescent neoformation (2 x 7 mm) of the right inguinal region, which was rehydrated and submitted to histology by hematoxylineosin, Van Gieson and Masson's trichromic staining. Light microscopy evidenced an exophytic, papillary skin lesion, with typical connective axis and pronounced parakeratosis. These macroscopic and histological aspects seemed peculiar of condyloma acuminatum, a papillomavirus-induced squamous lesion also called "venereal wart". Molecular study revealed the presence of HPV 18, a virus with high oncogenic potential. Automated sequencing of several clones revealed 100% similarity sequences of both HPV 18 and JC9813 DNA, a putative novel HPV with low oncogenic potential. This study represents the first molecular diagnosis of HPV in mummies and could pave the way for further research about the secular evolution of these viruses, very important in human oncology. The buccal surfaces of the teeth of Isabella d'Aragona, duchess of Milan ((1470-1524), covered by a black patina with high mercury levels, have been intensively and intentionally abraded. The black patina can be attributed to chronic mercury intoxication, used therapeutically in the treatment of syphilis. The mummy of Ferrante I d'Aragona, King of Naples (1431-1494), revealed an adenocarcinoma extensively infiltrating the muscles of the small pelvis. A molecular study of the neoplastic tissue evidenced a typical mutation of the K-ras gene codon 12: the normal sequence GGT (glycine) was altered into GAT (aspartic acid). At present this genetic change is the most frequent mutation of the K-ras gene in sporadic colorectal cancer. The alimentary "environment" of the Neapolitan court of the XV century, with its abundance of natural alimentary alkylating agents, well explains this acquired mutation. These and other diseases as, for example, a case of cirrhosis, some cases of anthracosis and other peculiar traumatic conditions, such as a mortal stab-wound, can elucidate the pathocenosis of this wealthy classes of the Italian Renaissance.
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PMID:[The Aragonese mummies of the Basilica of Saint Domenico Maggiore in Naples]. 1817 25


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