Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of our study was to determine the prevalence of the factor V mutation (position 1691 G-->A) in patients with angiographically diagnosed coronary artery disease and myocardial infarction and, as a control, in blood donors. This mutation has already been proved to be the main genetic risk factor for venous thrombosis. In order to detect this mutation in exon 10 of the factor V gene we established a microtiter plate based hybridization assay for the specific detection of wild-type and mutant sequences in factor V gene segments, obtained after amplification by polymerase chain reaction. This test enables us to screen a large number of samples. The mutation was detected in 29 of 317 coronary artery disease (CAD) patients (9.1%) and 18 of 190 blood donors (9.5%) investigated. The mean activated protein C resistance ratios were 3.18 and 3.11, with nearly identical distribution. No increased prevalence of the factor V mutation was found in the CAD group. In 10 of 29 CAD patients (35%) with the factor V 1691 G-->A mutation and in 124 of 288 CAD patients without the mutation (43%) there was a history of myocardial infarction. From our data we conclude that there is no increased risk of developing coronary atheroma or consecutive myocardial infarction resulting from the factor V mutation with protein C resistance.
J Mol Med (Berl) 1995 Oct
PMID:Evidence against heterozygous coagulation factor V 1691 G-->A mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction. 858 14

Considering the link between plasma high-density lipoprotein (HDL) cholesterol levels and a protective effect against coronary artery disease as well as the suggested beneficial effects of retinoids on the production of the major HDL apolipoprotein (apo), apo A-I, the goal of this study was to analyze the influence of retinoids on the expression of apo A-II, the other major HDL protein. Retinoic acid (RA) derivatives have a direct effect on hepatic apo A-II production, since all-trans (at) RA induces apo A-II mRNA levels and apo A-II secretion in primary cultures of human hepatocytes. In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels. Transient-transfection experiments with a reporter construct driven by the human apo A-II gene promoter indicated that 9-cis RA and at-RA, as well as the RXR agonists LGD 1069 and LG 100268, induced apo A-II gene expression at the transcriptional level. Only minimal effects of the RAR agonist TTNPB were observed on the apo A-II promoter reporter construct. Unilateral deletions and site-directed mutagenesis identified the J site of the apo A-II promoter mediating the responsiveness to RA. This element contains two imperfect half-sites spaced by 1 oligonucleotide. Cotransfection assays in combination with the use of RXR or RAR agonists showed that RXR but not RAR transactivates the apo A-II promoter through this element. By contrast, RAR inhibits the inductive effects of RXR on the apo A-II J site in a dose-dependent fashion. Gel retardation assays demonstrated that RXR homodimers bind, although with a lower affinity than RAR-RXR heterodimers, to the AH-RXR response element. In conclusion, retinoids induce hepatic apo A-II production at the transcriptional level via the interaction of RXR with an element in the J site containing two imperfect half-sites spaced by 1 oligonucleotide, thereby demonstrating an important role of RXR in controlling human lipoprotein metabolism. Since the J site also confers responsiveness of the apo A-II gene to fibrates and fatty acids via the activation of peroxisome proliferator-activated receptor-RXR heterodimers, this site can be considered a plurimetabolic response element.
Mol Cell Biol 1996 Jul
PMID:Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor. 866 50

Rapid discoveries of novel and unexpected disease-associated genes for atherosclerotic coronary artery disease (CAD) are anticipated as genomic maps become more detailed and methods for mapping complex disease phenotypes become more refined. Although establishing association or linkage of a marker locus to a CAD susceptibility gene is an important first step, the long-term goal should be to define the underlying functional mutations and explore possible disease mechanisms, including the gene-environment interactions that culminate in clinically apparent disease. This review will define a contemporary research paradigm for study of the genetics of CAD and other common chronic diseases using the tools of modern molecular biology and human genetics.
Hum Mol Genet 1996
PMID:Genetic analysis of atherosclerosis: a research paradigm for the common chronic diseases. 887 44

Angiotensin II has two major receptor subtypes, designated AT1 and AT2. Both have been detected in the heart of several species, but most of the known functions of angiotensin II seem to be mediated through the AT1 receptor. The major objective of this study was to specify the cell type on which the AT2 receptor is located in the atrium of human heart. Right atrial biopsies from patients with coronary artery disease were tested in membrane binding assays and found to contain high levels of angiotensin II receptor (820 +/- 175 fmol/mg), 82 +/- 2% of which was of the AT2 subtype. Cryostat sections of these biopsies were incubated with 125I-[Sar1,Ile8] angiotensin II in the presence of selective concentrations of the cold ligands losartan and CGP 42112A to detect the subtypes using microscopic autoradiography. High local densities of the AT2 receptor were observed. Comparison of the labelling patterns thus obtained with adjacent sections stained for vimentin, collagen, neurofilaments or acetylcholinesterase revealed that the high densities of AT2 receptor were always associated with fibrous tissue. However, the AT1 receptor was in general evenly distributed over the tissue at low concentrations. Higher local concentrations of this receptor subtype were observed on nervous tissue. The present finding of high densities of the AT2 receptor on fibroblasts at sites of fibrosis may have important clinical implications. Further studies to elucidate the function of this receptor subtype in the heart are therefore essential and the clinical consequences of the use of AT1 antagonists on post-infarction remodelling should be investigated.
J Mol Cell Cardiol 1996 Aug
PMID:Localization of the angiotensin II receptor subtypes in the human atrium. 887 88

The activity and immunocytochemical localization of cathepsin D in the frontal cortex were investigated in patients with Alzheimer disease (AD) and two groups of nondemented subjects; individuals with critical coronary artery disease (cCAD; > 75% stenosis) and non-heart disease controls (non-HD). The cathepsin D activity significantly increased with age in the non-HD population. No such age-related increase was observed in either AD or cCAD. Enzymatic activity was significantly increased in only the midaged, but not the older AD and cCAD subjects compared to controls. Immunocytochemical reactivity paralleled cathepsin D enzymatic activity. Frontal cortex neurons displayed an increased accumulation of cathepsin D immunoreactivity in aging (non-HD controls) with a further increase in cCAD, especially in the midaged group. Such immunoreactivity was markedly increased in AD. There was also an apparent age-related increase in the number of cathepsin D immunoreactive neurons in the non-HD population and a disease-related increase in only the mid-aged AD and cCAD subjects compared to controls. Senile plaques (SP) occurred in all AD patients, many cCAD, and a few of the oldest non-HD subjects, and they were immunoreactive to cathepsin D in each group. The data suggest a possible relationship between activation of cathepsin D and SP formation in AD, cCAD, and aging.
Mol Chem Neuropathol 1996 Sep
PMID:Cortical cathepsin D activity and immunolocalization in Alzheimer disease, critical coronary artery disease, and aging. 888 36

The purpose of the study was to investigate changes in serum ubiquinol/ubiquinone ratio with copper ion induced oxidative stress, and to assess the ubiquinol/ubiquinone ratio as marker of in vivo oxidative stress in patients with coronary artery disease (CAD). Plasma ubiquinol, ubiquinone, vitamin E (alpha-tocopherol) and total cholesterol (TC) concentrations were measured in 40 patients with angiographically confirmed coronary artery disease and 100 apparently healthy controls. The mean (SD) ubiquinol/ubiquinone ratio of 26.5 (7.5) of the CAD patients was significantly lower than the mean ratio of 30.2 (8.8) of the controls (p = 0.02). Our results indicate that the ubiquinol/ubiquinone ratio is a sensitive marker of oxidative stress and that an altered ubiquinol/ubiquinone ratio is the first sign of lipoprotein exposure to oxidative stress. The altered ratio in CAD patients cannot be explained by differences in plasma vitamin E levels. The vitamin E concentrations were in fact significantly higher in CAD patients, and did not appear to protect the ubiquinol from increased oxidation due to free radical reactions. These results may indicate that circulating lipoproteins of CAD patients are more exposed to, or are more susceptible to, free radical reactions compared with apparently healthy controls.
Res Commun Mol Pathol Pharmacol 1997 Jan
PMID:Ubiquinol/ubiquinone ratio as marker of oxidative stress in coronary artery disease. 905 45

Carbamoyl-phosphate synthase/aspartate carbamoyltransferase/dihydroorotase, which is encoded by the cad gene, is required for the first three rate-limiting steps of de novo pyrimidine biosynthesis. It has been previously demonstrated that cad transcription increases at the G1/S-phase boundary, as quiescent cells reenter the proliferative cell cycle. The growth-responsive element has been mapped to an E box at +65 in the hamster cad promoter. Using an in vivo UV cross-linking and immunoprecipitation assay, we show that Myc, Max, and upstream stimulatory factor (USF) bind to the chromosomal cad promoter. To determine whether binding of Myc-Max or USF is critical for cad growth regulation, we analyzed promoter constructs which contain mutations in the nucleotides flanking the E box. We demonstrate that altering nucleotides which flank the cad E box to sequences which decrease Myc-Max binding in vitro correlates with a loss of cad G1/S-phase transcriptional activation. This result supports the conclusion that binding of Myc-Max, but not USF, is essential for cad regulation. Our investigations demonstrate that the endogenous cad E box can be bound by more than one transcription factor, but growth-induced cad expression is achieved only by Myc.
Mol Cell Biol 1997 May
PMID:Myc versus USF: discrimination at the cad gene is determined by core promoter elements. 911 22

Ser1406 of the allosteric region of the hamster CAD enzyme, carbamyl phosphate synthetase II (CPSase), is known to be phosphorylated in vitro by cAMP-dependent protein kinase (PKA). Metabolic labeling experiments described here demonstrate that CAD is phosphorylated in somatic cells in culture. Phosphorylation is stimulated by treating cells with 8-bromo-cAMP, a PKA activator. The stimulation is essentially prevented by pretreatment with H-89, a PKA specific inhibitor. Substitution of Ser1406 with alanine results in an enzyme with kinetics and allosteric regulation indistinguishable from unsubstituted CAD. However, substitution to glutamic acid increases CPSase activity by reducing the apparent Km (ATP). The UTP concentration required to give 50% inhibition is increased rendering this altered enzyme significantly less sensitive to feedback inhibition, but allosteric activation by PRPP is unaffected. While these data do not prove that Ser1406 is phosphorylated in vivo, they do indicate that a specific alteration at this residue can affect allosteric regulation.
Somat Cell Mol Genet 1997 Jan
PMID:Site-directed substitution of Ser1406 of hamster CAD with glutamic acid alters allosteric regulation of carbamyl phosphate synthetase II. 921

The oxidation of low density lipoprotein (LDL) is now commonly regarded as an important early event in atherogenesis. As such there is considerable interest in the ability of antioxidant supplementation to attenuate LDL oxidation and hence atherosclerosis. A majority of studies on LDL antioxidation have focused on alpha-tocopherol (alpha-TOH), biologically and chemically the most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. In addition to alpha-TOH, circulating LDL also contains low levels of ubiquinol-10 (CoQ10H2; the reduced form of coenzyme Q). Recent studies have shown that in intact, isolated LDL, alpha-TOH can act as either an anti- or prooxidant for the lipoprotein's lipids. This article reviews the molecular action of alpha-TOH in LDL undergoing radical-initiated oxidation, and how the presence of CoQ10H2 suppresses the pro-oxidant or complements the antioxidant activity of the vitamin. We also comment on the plasma and intimal levels of alpha-TOH and CoQ10H2 in patients suffering from coronary artery disease and discuss the potential implications of these results for atherogenesis.
Mol Aspects Med 1997
PMID:Inhibition of LDL oxidation by ubiquinol-10. A protective mechanism for coenzyme Q in atherogenesis? 926 10

Estrogen protects against developing premature coronary artery disease. However, the mechanism of protective effects of estrogen still remains poorly understood. One mechanism by which estrogen can have protective effects appears to be through modulation of plasma lipoproteins. We showed that the mouse can be used as animal model to study estrogen-mediated synthesis and secretion of lipoproteins since, unlike the rat, the mouse does not up-regulate LDL receptors (Srivastava et al. [4]). Since inbred strains of mice differ in their genetic background and show differing responsiveness to dietary lipids, we examined how various inbred strains of mice respond to estradiol administration, and whether some mouse strains show responses similar to rats. 17beta-estradiol was administered to male mice from 15 different inbred strains, and the changes in plasma levels of lipids, apoB, apoAI, and apoE were examined. Total cholesterol decreased in all but one strain, apoAI levels decreased in all but 3 strains while apoB levels and apoB/apoAI ratios increased in all but 2 strains, suggesting that in contrast to rats, the apoB-containing lipoproteins increased relative to HDL in all strains of mice examined. Basal and estradiol-induced changes in total cholesterol were significantly correlated with changes in apoAI, but not apoB, reflecting the predominance of HDL over other lipoproteins in mouse plasma. The effects of estrogen on plasma apoE levels varied among various inbred strains of mice tested. Plasma apoE levels increased in seven strains treated with estrogen, and remained unchanged in the rest. To examine whether changes of plasma apoproteins are associated with the changes in the respective hepatic mRNA levels, apoAI, B and E mRNA were quantified by RNase protection assay. Hepatic apoE mRNA did not show correlation with either basal or post treatment plasma apoE levels in any of the strains. Similarly, most of the mouse strains did not show correlation of plasma apoAI and apoB levels with the corresponding hepatic mRNA levels. These results suggest that estrogen regulates plasma lipoprotein concentrations primarily by posttranscriptional mechanisms, and there were strain-related differences in the estrogen-mediated regulation of lipoprotein metabolism.
Mol Cell Biochem 1997 Aug
PMID:Regulation of lipoprotein metabolism by estrogen in inbred strains of mice occurs primarily by posttranscriptional mechanisms. 927 67


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