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Y Y van der Hoek

Publications and source records attributed to Y Y van der Hoek.

12 recordsLinked to original sources
PubMed2003

Changes of plasma lipoprotein(a) during and after normal pregnancy in Caucasians.

OBJECTIVE: Elevated plasma concentrations of lipoprotein(a) are associated with an increased risk for development of atherosclerosis. High lipoprotein(a) concentrations may also be associated with pregnancy-induced hypertension and pre-eclampsia, but reference data on the course of lipoprotein(a) during uneventful pregnancies are limited and questionable. METHODS: We studied plasma lipoprotein(a) concentrations in 19 healthy nulliparous Caucasian women during and after uncomplicated pregnancy. Blood was sampled every 4 weeks during pregnancy from 9 weeks onwards, during labor and at 2-4 weeks and 3-5 months after delivery. An apolipoprotein(a) (apo(a)) isoform-independent enzyme-linked immunosorbent assay (ELISA) was used to measure lipoprotein(a). Multilevel analysis was used to describe the data. RESULTS: Lipoprotein(a) increased until 35 weeks, subsequently decreased slightly until delivery, and fell to values below early pregnancy concentrations thereafter. The curve is defined by the formula lipoprotein(a) (mg/l) = exp [4.789 + (0.05215 x GA) + (-0.0007371 x GA2)] where GA = gestational age in weeks. CONCLUSIONS: We constructed a curve for plasma lipoprotein(a) which may serve as the standard reference for changes in pregnancy. Its formula is helpful in predicting changes of gestational age-dependent changes of lipoprotein(a) in normal pregnancy.

Adult↗
PubMed1998

The functional and clinical significance of the Met-->Thr substitution in Kringle IV type 10 of apolipoprotein(a).

Lipoprotein(a) [Lp(a)], an independent risk factor for the development of atherosclerosis, contains an apolipoprotein(a) [apo(a)] moiety covalently linked to a LDL moiety. Apo(a) is a glycoprotein homologous to plasminogen as it contains multiple repeats of a lysine binding domain resembling plasminogen kringle IV (K.IV). The multiple K.IV repeats can be differentiated in ten types that show a variation in their lysine binding capacity. Since K.IV type 10 shows the highest conservation of the amino acids postulated to form the lysine binding pocket, this kringle is suggested to be the main lysine binding site of apo(a). Recently, a T-->C polymorphism in the apo(a)-gene was reported, leading to a Met-->Thr substitution at amino acid position 66 of K.IV type 10, in the vicinity of the postulated lysine binding pocket. To investigate the significance of this substitution on some in vitro characteristics of Lp(a), the affinity for lysine-Sepharose and the binding affinity for limited plasmin digested des AA fibrin (Desafib-X) of the two subtypes was determined using plasma of donors homozygous for the polymorphism. These studies revealed a large heterogeneity in the binding characteristics, irrespective of the subtype. The comparison of the allele frequencies of this polymorphism in 155 patients having symptomatic atherosclerosis versus 153 normolipidemic controls revealed no significant differences. In conclusion, this study suggests that the presence of either a Met66 or a Thr66 residue in K.IV type 10 of apo(a) has no consequences for the binding characteristics of Lp(a) toward lysine-Sepharose or Desafib-X, nor is it associated with the presence of symptomatic atherosclerosis.

Adult↗
PubMed1997

Sib-pair analysis detects elevated Lp(a) levels and large variation of Lp(a) concentration in subjects with familial defective ApoB.

Whether or not Lp(a) plasma levels are affected by the apoB R3500Q mutation, which causes Familial Defective apoB (FDB), is still a matter of debate. We have analyzed 300 family members of 13 unrelated Dutch index patients for the apoB mutation and the apolipoprotein(a) [apo(a)] genotype. Total cholesterol, LDL-cholesterol, and lipoprotein(a) [Lp(a)] concentrations were determined in 85 FDB heterozygotes and 106 non-FDB relatives. Mean LDL levels were significantly elevated in FDB subjects compared to non-FDB relatives (P < 0.001). Median Lp(a) levels were not different between FDB subjects and their non-FDB relatives. In contrast, sib-pair analysis demonstrated a significant effect of the FDB status on Lp(a) levels. In sib pairs identical by descent for apo(a) alleles but discordant for the FDB mutation (n = 11) each sib with FDB had a higher Lp(a) level than the corresponding non-FDB sib. Further, all possible sib pairs (n = 105) were grouped into three categories according to the absence/presence of the apoB R3500Q mutation in one or both subjects of a sib pair. The variability of differences in Lp(a) levels within the sib pairs increased with the number (0, 1, and 2) of FDB subjects present in the sib pair. This suggests that the FDB status increases Lp(a) level and variability, and that apoB may be a variability gene for Lp(a) levels in plasma.

Adult↗
PubMed1997

The identification and significance of a Thr-->Pro polymorphism in kringle IV type 8 of apolipoprotein(a).

Elevated plasma levels of lipoprotein(a) [Lp(a)] represent a significant independent risk factor for the development of atherosclerosis. Interindividual levels of apo(a) vary over 1000-fold and are mainly due to inheritance that is linked to the locus of the apolipoprotein(a) [apo(a)] gene. The apo(a) gene encodes multiple repeats of a sequence exhibiting up to 85% DNA sequence homology with plasminogen kringle IV (K.IV), a lysine binding domain. In our search for sequence polymorphisms in the K.IV coding domain, we identified a polymorphism predicting a Thr-->Pro substitution located at amino acid position 12 of kringle IV type 8 of apo(a). The functional and clinical significance of this polymorphism was analysed in a case-control study and by comparing the in vitro lysine binding characteristics of the two Lp(a) subtypes. The case-control study (involving 153 subjects having symptomatic atherosclerosis and 153 age and gender matched normolipidemic controls) revealed a overall allele frequency for the Thr12-->Pro substitution in kringle IV type 8 of 14% and a negative association between presence of the Pro12-subtype and symptomatic atherosclerosis (p < 0.03). The in vitro lysine binding studies, using Lp(a) isolated from subjects homozygous for either Thr12 or Pro12 in K.IV type 8, revealed comparable lysine-Sepharose binding fractions for the two subtypes. The binding affinity (Kd) for immobilised plasmin degraded des-AA-fibrin (Desafib-X) was also comparable for the two subtypes, however a decreased maximal attainable binding (Bmax) for immobilised desafib-X was observed for the Pro12-subtype Lp(a).

Adult↗
PubMed1997

Lipoprotein[a] is not present in the plasma of patients with some peroxisomal disorders.

Peroxisomal disorders arise either from defects in the biogenesis of peroxisomes or from the defective synthesis of one or more peroxisomal enzymes. These defects result in metabolic disturbances in peroxisomal beta-oxidation of various fatty acids and derivatives and/or in the biosynthesis of ether lipids. In the current study, lipoprotein levels were determined in plasma samples from patients diagnosed with one of four different peroxisomal disorders. While low density lipoprotein (LDL) levels were found to be within the normal range, lipoprotein[a] (Lp[a]) could not be detected by enzyme-linked immunosorbent assay (ELISA) in plasma from patients with cerebro-hepato-renal (Zellweger) syndrome (ZS) and rhizomelic chondrodysplasia punctata (RCDP). Conversely, Lp[a] was clearly present in control plasma obtained from healthy newborns and from patients affected with one of two other peroxisomal disorders, X-linked adrenoleukodystrophy (X-ALD) and Refsum disease (RD) as determined by ELISA. The lack of Lp[a] in plasma of patients with ZS may result from defective secretion of apolipoprotein[a] (apo[a]) (the distinguishing protein component of Lp[a]), as apo[a] mRNA transcripts were clearly present in ZS livers as assessed by PCR, and intracellular apo[a] protein was detected in total liver homogenates from ZS patients as determined by Western blot analysis. Furthermore, LDL present in the plasma of ZS patients was able to associate with recombinant apo[a] in an in vitro Lp[a] assembly assay.

Adolescent↗
PubMed1996

Lipoprotein [a].

Explore the source record for details and available documents.

Alleles↗
PubMed1994

Analysis of structure--function relationships in human apolipoprotein(a).

Elevated levels of lipoprotein(a) (Lp(a)) have been strongly correlated with the development of atherosclerosis in human populations. Lp(a) is distinguishable from low density lipoprotein by the presence of the unique protein component apolipoprotein(a) (apo(a)), which contains repeated domains that closely resemble that of plasminogen kringle IV. Using human embryonic kidney cells, we have expressed a recombinant form of apo(a) (r-apo(a)) containing 17 kringle IV-like domains. We have utilized this recombinant expression system to study the assembly of Lp(a) particles. We have demonstrated that Lp(a) particles containing r-apo(a) can be assembled extracellularly in plasma by covalent linkage to low density lipoprotein. Using site-directed mutagenesis, we have demonstrated that a cysteine residue present at position 4057 of the apo(a) protein (i.e., in the penultimate kringle IV repeat) mediates this covalent linkage. Using polymerase chain reaction amplification of liver apo(a) complementary DNA, we have demonstrated the presence of a polymorphism in apo(a) kringle IV type 10, which results in the substitution of a threonine for a methionine. Preliminary studies indicate that the presence of a threonine at this position may enhance the interaction of Lp(a) with lysine-Sepharose.

Animals↗
PubMed1994

Binding of recombinant apolipoprotein(a) to extracellular matrix proteins.

Elevated levels of lipoprotein(a), which consists of apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein-like moiety, is an independent risk factor for the development of atherosclerosis. We show that a recombinant form of apo(a) [r-apo(a)] binds strongly to fibronectin and fibrinogen, weakly to laminin, and not at all to von Willebrand factor, vitronectin, or collagen type IV. In contrast to the binding of plasminogen to fibronectin, r-apo(a) binding does not appear to be mediated by lysine-dependent interactions, based on the inability of epsilon-aminocaproic acid concentrations up to 0.2 mol/L to significantly decrease r-apo(a) binding to fibronectin. Plasminogen competed weakly for the binding of r-apo(a) to fibronectin, whereas r-apo(a) completely abolished plasminogen binding. The 29- and 38-kd heparin-binding thermolysin fragments of fibronectin, previously identified as the lipoprotein(a) binding domains, were digested with trypsin, and a peptide that retained the ability to bind r-apo(a) was isolated; the sequence of the peptide (AVTTIPAPTDLK) corresponds to the amino terminus of the 29- and 38-kd domains. A synthetic peptide with this sequence was able to compete effectively with fibronectin for r-apo(a) binding.

Aminocaproates↗
PubMed1993

Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100.

We have utilized a recombinant expression system in order to study the assembly of lipoprotein(a) (Lp(a)) particles. Using a 17-kringle recombinant form of apolipoprotein(a) (apo(a)) to transiently transfect human hepatoma cells, we could not detect recombinant Lp(a) (r-Lp(a)) particles intracellularly, by analysis of postnuclear lysates. However, covalent r-Lp(a) complexes were observed in the transfected cell supernatants. Upon addition of [35S]Cys-labeled human embryonic kidney cell supernatants transfected with 9-kringle or 17-kringle recombinant apo(a) (r-apo(a)) variants to human plasma, covalent r-Lp(a) complexes were observed, which could be immunoprecipitated using antibodies specific for either apo(a) or apolipoprotein B-100 (apoB-100); r-Lp(a) complexes containing the 17-kringle r-apo(a) were shown to be in the 1.063 g/ml < d < 1.20 g/ml range by density gradient ultracentrifugation analysis. Complexes containing the 17-kringle r-apo(a) formed rapidly within 20 min, with a slow increase observed up to 90 min. Addition of increasing amounts of plasma, as well as increasing amounts of isolated human low density lipoprotein to cell culture supernatants containing [35S]Cys-labeled 17-kringle r-apo(a) led to enhanced r-Lp(a) complex formation. Blocking of free sulfhydryls in apo(a) with N-ethylmaleimide resulted in inhibition of r-Lp(a) complex formation in plasma, verifying the role of free sulfhydryls in Lp(a) particle assembly. Using site-directed mutagenesis, we demonstrated that Cys4057 in apo(a) is involved in disulfide linkage with apoB-100 in Lp(a) particles.

Amino Acid Sequence↗
PubMed1993

The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms.

Elevated levels of plasma lipoprotein(a) [Lp(a)] have been correlated with the development of atherosclerosis in human populations. Apolipoprotein(a) [apo(a); the distinguishing protein component of Lp(a)] is characterized by multiple repeats of a sequence that closely resembles kringle IV of plasminogen. Variably-sized Lp(a) isoforms that are observed in the human population have been shown to occur as a result of differences in the numbers of the repeated kringle IV units in apo(a). Using PCR analysis of human liver mRNA, we have analyzed apo(a) from 10 unrelated individuals in order to determine the presence or absence of kringle IV repeat #1, and #30-#37. Based on the apo(a) cDNA sequence published for one individual, these kringles all differ to some degree in amino acid sequence from the major kringle IV repeat, which is present in a number of identically repeated copies. We found that sequences corresponding to apo(a) kringle IV repeat #1, and #30-#37 were present in all individuals studied. This suggests that the inverse relationship that has been observed between Lp(a) isoform size and plasma Lp(a) levels is mediated by different numbers of identical kringle IV repeats, by an as yet undetermined mechanism. During the course of this study, we identified a Met-->Thr polymorphism in the apo(a) kringle IV repeat #37. The calculated frequencies of the Met and Thr alleles were 0.58 and 0.42 respectively. We did not observe a correlation between the Met-->Thr substitution and either plasma Lp(a) levels, or apo(a) transcript size.

Amino Acid Sequence↗
PubMed1991

Details of mannitol transport in Escherichia coli elucidated by site-specific mutagenesis and complementation of phosphorylation site mutants of the phosphoenolpyruvate-dependent mannitol-specific phosphotransferase system.

The mannitol transport protein (EIImtl) carries out translocation with concomitant phosphorylation of mannitol from the periplasm to the cytoplasm, at the expense of phosphoenolpyruvate (PEP). The phosphoryl group which is needed for this group translocation is sequentially transferred from PEP via two phosphorylation sites, located exclusively on the C-terminal cytoplasmic domain, to mannitol. Oligonucleotide-directed mutagenesis was used to investigate the precise role of these sites in phosphoryl group transfer, by producing specific amino acid substitutions. The first phosphorylation site, His-554 (P1), was replaced by Ala, which renders the EII-H554A completely inactive in PEP-dependent mannitol phosphorylation, but not in mannitol/mannitol 1-phosphate exchange. The P2 site mutant, EII-C384S, was inactive both in the mannitol phosphorylation reaction and in the exchange reaction, due to replacement of the essential Cys-384 by Ser. Although EII-H554A and EII-C384S were both catalytically inactive in the PEP-dependent phosphorylation, EII-C384S was able to restore up to 55% of the wild-type mannitol phosphorylation activity with the EII-H554A mutant, indicating a direct phosphotransfer between two subunits. These phosphorylation data together with the data obtained from mannitol/mannitol phosphate exchange kinetics, after mixing EII-H554A and EII-C384S, indicated the formation of functionally stable heterodimers, which consist of an EII-H554A and an EII-C384S monomer.

Base Sequence↗