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H J van Rijn

Publications and source records attributed to H J van Rijn.

At least 19 recordsLinked to original sources
PubMed2001

Lysophosphatidic acid-independent platelet activation by low-density lipoprotein.

Mildly oxidized low-density lipoprotein activates platelets through lysophosphatidic acid (LPA). Hence, the platelet-activating properties attributed to native low-density lipoprotein (nLDL) might be caused by LPA contamination. We show that nLDL enhances thrombin receptor-activating peptide (TRAP)-induced fibrinogen binding to alpha(IIb)beta(3). The LPA receptor blocker N-palmitoyl-L-serine-phosphoric acid did not affect nLDL-enhanced fibrinogen binding induced by TRAP, but reduced TRAP-induced binding. cAMP and inhibitors of protein kinase C and Ca(2+) rises completely blocked ligand binding by TRAP and nLDL/TRAP. Inhibitors of p38(MAPK) and ADP secretion interfered only partially. Blockade of Rho-kinase increased ligand binding 2-3-fold. We conclude that nLDL enhances TRAP-induced fibrinogen binding independent of LPA.

Adenosine Diphosphate↗
PubMed2000

Low-density lipoprotein activates the small GTPases Rap1 and Ral in human platelets.

Physiological concentrations of low-density lipoprotein (LDL) sensitize blood platelets to alpha-thrombin- and collagen-induced secretion, and after prolonged contact trigger secretion independent of other agonists. Here we report that LDL activates the small GTPases Rap1 and Ral but not Ras, as assessed by specific precipitation of the GTP-bound enzymes. In unstirred suspensions, the inhibitor SB203580 blocks Rap1 activation by 60-70%, suggesting activation via p38 mitogen-activated protein kinase and a second, unidentified route. Inhibitors of cyclooxygenase (indomethacin) and the thromboxane A(2) (TxA(2)) receptor (SQ30741) induce complete inhibition, indicating that Rap1 activation is the result of TxA(2) formation. Stirring reveals a second, TxA(2)-independent Rap1 activation, which correlates quantitatively with a slow induction of dense granule secretion. Both pathways are unaffected by inhibitors of ligand binding to integrin alpha(IIb)beta(3). The results suggest that Rap1 and Ral, but not Ras, may take part in signalling routes initiated by LDL that initially enhance the sensitivity of platelets to other agonists and later trigger LDL-dependent secretion.

Arachidonic Acid↗
PubMed1999

Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125(FAK) in human platelets independent of integrin alphaIIb beta3.

Low density lipoprotein (LDL) is known to sensitize platelets to agonists via integrin mediated outside-in signaling (Hackeng, C. M., Huigsloot, M., Pladet, M. W., Nieuwenhuis, H. K., Rijn, H. J. M. v., and Akkerman, J. W. N. (1999) Arterioscler. Thromb. Vasc. Biol., in press). As outside in signaling is associated with phosphorylation of p125(FAK), the effect of LDL on p125(FAK) phosphorylation in platelets was investigated. LDL induced p125(FAK) phosphorylation in a dose- and time- dependent manner. The phosphorylation was independent of ligand binding to integrin alphaIIbbeta3 and aggregation, such in contrast to alpha-thrombin-induced p125(FAK) phosphorylation, that critically depended on platelet aggregation. Platelets from patients with Glanzmann's thrombastenia showed the same LDL- induced phos- phorylation of p125(FAK) as control platelets, whereas alpha-thrombin completely failed to phosphorylate the kinase in the patients platelets. LDL signaling to p125(FAK) was independent of integrin alpha2 beta1, the FcgammaRII receptor, and the lysophosphatidic acid receptor and not affected by inhibitors of cyclooxygenase, protein kinase C, ERK1/2 or p38(MAPK). Phosphorylation of p125(FAK) by LDL was strongly inhibited by cyclic AMP. These observations indicate that LDL is a unique platelet agonist, as it phosphorylates p125(FAK) in platelet suspensions, under unstirred conditions and independent of integrin alphaIIb beta3.

Blood Platelets↗
PubMed1999

Low-density lipoprotein enhances platelet secretion via integrin-alphaIIbbeta3-mediated signaling.

LDL is known to increase the sensitivity of human platelets for agonists and to induce aggregation and secretion independently at high concentrations, but its mechanism of action is largely obscure. To clarify how LDL increases platelet sensitivity, cells were incubated in lipoprotein-poor plasma and treated with collagen at a concentration that induced approximately 20% secretion of 14C-serotonin. Preincubation with LDL (30 minutes at 37 degreesC) enhanced secretion in a dose-dependent manner to 60+/-14% at a concentration of 2 g LDL protein/L. Similar stimulation by LDL was seen when secretion was induced by the thrombin receptor-activating peptide. This enhancement was strongly reduced (1) in the presence of monoclonal antibody PAC1 against activated alphaIIbbeta3, a polyclonal antibody against alphaIIb, and in the presence of the fibrinogen peptides GRGDS and HHLGGAKQAGDV; (2) in alphaIIbbeta3-deficient platelets; and (3) after dissociation of alphaIIbbeta3. In contrast, binding of 125I-LDL to normal platelets in the presence of PAC1, anti-alphaIIb, GRGDS, and HHLGGAKQAGDV, and to alphaIIbbeta3-deficient platelets was normal. LDL increased the surface expression of fibrinogen in lipoprotein-poor plasma and fibrinogen-free medium, suggesting that extracellular and granular fibrinogen bind to alphaIIbbeta3 after platelet-LDL interaction. Platelets deficient in fibrinogen (<0.5% of normal) or von Willebrand Factor (<1% of normal) but containing normal amounts of other ligands for alphaIIbbeta3 preserved responsiveness to LDL, indicating that occupancy of alphaIIbbeta3 was not restricted to fibrinogen. Inhibition of protein kinase C (bisindolylmaleimide) diminished fibrinogen binding and sensitization by LDL; inhibition of tyrosine kinases (herbimycin A) left fibrinogen binding unchanged but diminished sensitization by LDL. We conclude that an increased concentration of LDL, such as observed in homozygous familial hypercholesterolemia, sensitizes platelets to stimulation by collagen and thrombin receptor-activating peptide via ligand-induced outside-in signaling through integrin-alphaIIbbeta3.

Blood Platelets↗
PubMed1999

The identification of polymorphisms in the coding region of the apolipoprotein (a) gene--association with earlier identified polymorphic sites and influence on the lipoprotein (a) concentration.

Lipoprotein (a) [Lp(a)] is a quantitative genetic trait in human plasma and elevated levels represent a major inherited risk factor for the development of atherosclerotic disease. In our search for sequence polymorphisms in the coding region of the apolipoprotein(a) [apo(a)] gene that may affect the Lp(a) concentration, four new polymorphic sites were identified. These include two coinciding polymorphisms with an allele frequency of 38% located at amino acid positions 87 and 101 (Leu87,101-->Val) in the interkringle region of kringle IV (K.IV) type 7 and two polymorphisms located in K.IV type 7 (Arg60-->Ser) and in K.IV type 10 (Tyr2-->Phe) both with estimated allele frequencies of about 1%. The linkage between the newly identified K.IV type 7 Leu87,101 -->Val polymorphism and earlier described polymorphic sites in the non-coding and coding regions of the apo(a) gene, its distribution over the apo(a) isoform sizes and its possible influence on the Lp(a) concentration was analysed in 201 healthy unrelated Caucasians. The earlier described polymorphic sites included in this study were the variable number of a TTTTA pentanucleotide repeat (7-11 PNR) starting at -1231 bp, the -772 bp G/A polymorphism, the +93 bp C/T polymorphism and the +121 bp G/A polymorphism in the non-coding region, and the K.IV type 8 Thr12/Pro polymorphism and the K.IV type 10 Thr66/Met polymorphism in the coding region of the apo(a) gene. Linkage disequilibria were observed between the polymorphic sites in the 5' non-coding region and the sites in K.IV type 7 and 8 in the coding region of the apo(a) gene, confirming that the expansion of the variable number of K.IV type 2 repeats results from intrachromosomal recombinational events. The distribution over the apo(a) isoform sizes of the K.IV type 7 Val87,101 subtype was not significantly different from that of the K.IV type 7 Leu87,101 wild-type, suggesting a relative ancient mutational event. No influence of the K.IV type 7 Leu87,101-->Val polymorphism on the Lp(a) level was observed. In fact, of all the polymorphic sites studied, only the +121 A subtype could be associated with an increased, and the K.IV type 8 Pro12 and the 10 PNR subtypes with a reduced, Lp(a) concentration corrected for apo(a) isoform size (p <0.05).

Alleles↗
PubMed1999

Early platelet activation by low density lipoprotein via p38MAP kinase.

Low Density Lipoprotein (LDL) is known to sensitize platelets for physiological agonists. To clarify the basis of this sensitization, we investigated the involvement of p38MAP Kinase (p38MAPK). As dual phosphorylation on Thr180 and Tyr182 of p38MAPK is the trigger for activation of the kinase, p38MAPK-activity was measured with an antibody that recognizes the dual-phosphorylated sequence. LDL induced a rapid and dose dependent activation of p38MAPK. The activation was not inhibited by a wide variety of inhibitors of platelet signalling, including TxA2-formation, Phospholipase C-activation, Ca2+-mobilization and ERK 1/2-activation. Only a slight reduction in p38MAPK-activation was observed when protein kinase C was inhibited. Activation of p38MAPK was strongly inhibited by a rise in cAMP. Thus, p38MAPK-activation was upstream of most signalling pathways and close to the LDL-receptor. A number of platelet receptors was screened with the use of antibodies. Integrins alphaIIbbeta3 and alpha2beta1, as well as the FcgammaRII-receptor, CD36 (platelet glycoprotein IV), CD68 (gp110) and Low Density Lipoprotein-receptor related protein (LRP) were not implicated in LDL-induced p38MAPK-activation. Inhibition of LDL binding by modification of apo B100 lysines reduced p38MAPK-activation by 80%. Activation of p38MAPK resulted in an increase in release of arachidonic acid, the precursor for thromboxane A2 synthesis. In conclusion, activation of p38MAPK might be the first step in platelet sensitization by LDL, leading to formation of arachidonate metabolites and increased aggregation and secretion responses to physiological agonists.

Humans↗
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↗
PubMed1998

Assessment of nitric oxide production by measurement of [15N]citrulline enrichment in human plasma using high-performance liquid chromatography-mass spectrometry.

Nitric oxide (NO) is formed by a class of NO synthases (NOS), which convert arginine into citrulline. A decreased in vivo NO availability can be the result of an increased NO inactivation or a decreased NO production. The latter can be assessed by measurement of isotopic enrichment of plasma citrulline during infusion of isotopically labeled arginine. The potential of high-performance liquid chromatography (HPLC) coupled to mass spectrometry (MS) to determine enrichments of [15N2]arginine and [15N]-citrulline in plasma during infusion of [15N2]arginine in humans was investigated. Two types of MS instruments were evaluated: a sector-type mass spectrometer equipped with a frit fast-atom bombardment (FAB) interface and a quadrupole instrument with electrospray ionization (ESI). FAB-MS appeared to be unsuitable for determination of isotope ratios, because background ions influenced the observed isotope ratio in an unpredictable way. In combination with either off- or on-line reversed-phase HPLC, ESI-MS proved to be a more reliable technique. However, the amount of material that is introduced in the mass spectrometer is critical and should be carefully controlled. During infusion of [15N2]arginine in 14 healthy subjects, a mean arginine-to-citrulline conversion rate of 0.22 +/- 0.07 (SD) mumol.kg-1.h-1 was found. In 4 subjects who received an intravenous infusion with the NOS antagonist L-NMMA, the conversion rate decreased from 0.30 +/- 0.14 to 0.10 +/- 0.06 mumol.kg-1.h-1. It is concluded that ESI-MS in combination with HPLC can be successfully applied for determination of arginine and citrulline enrichments in plasma, thus providing a useful tool for assessment of in vivo NO production.

Chromatography, High Pressure Liquid↗
PubMed1998

Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients.

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 +/- 0.07 vs 0.78 +/- 0.08 mmol l(-1), p < 0.05), as was Mg excretion (5.5 +/- 1.9 vs 3.7 +/- 1.4 mmol 24 h(-1), p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 +/- 3.8 vs 11.6 +/- 6.2 mmol l(-1), p = 0.8; HbA1c: 8.9 +/- 1.6 vs 9.1 +/- 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: -4.0 +/- 10.1 vs +2.5 +/- 12.0 mmHg, p = 0.059). Three months' oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations.

Administration, Oral↗
PubMed1998

Effect of an increase in the plasma potassium concentration on renal magnesium handling in healthy volunteers.

BACKGROUND: Lower plasma magnesium concentrations are associated with clinical problems such as arrhythmias and hypertension. Plasma magnesium concentration is tightly controlled by the kidney. Modifying renal magnesium threshold may provide a means to increase the plasma magnesium concentration. Since evidence has been presented that potassium deficiency by itself may increase renal magnesium loss, the hypothesis that elevating plasma potassium would result in an increase in plasma magnesium concentration was tested in healthy volunteers. METHODS: Plasma potassium was raised in nine healthy volunteers by oral administration of 20 mg amiloride daily during 3 weeks. Magnesium metabolism was assessed before and after this period by plasma levels, urinary magnesium excretion and fractional magnesium excretion, and magnesium loading test (MLT). This MLT allows calculation of renal retention of a magnesium load. RESULTS: Basal plasma magnesium levels (0.84 +/- 0.07 vs 0.84 +/- 0.05 mmol/l) as well as urinary magnesium excretion (4.37 +/- 1.73 vs 3.67 +/- 1.37 mmol/day) and erythrocyte magnesium levels (1.72 +/- 0.16 vs 1.76 +/- 0.14 mmol Mg/l red blood cells) were similar before and on amiloride. Plasma potassium rose significantly on amiloride (3.64 +/- 0.24 vs 4.07 +/- 0.54 mmol/l, P < 0.05). No change was observed in magnesium retention with the MLT: 22.7 +/- 26.7 vs 29.2 +/- 20.6% (P = 0.5). CONCLUSIONS: Despite an increased plasma potassium concentration, no change was observed in plasma magnesium levels, urinary magnesium excretion or renal magnesium retention of an intravenously administered magnesium load. This indicates that increasing plasma potassium within the normal range does not modify the renal magnesium threshold.

Adult↗
PubMed1998

Acute exogenous elevation of plasma free fatty acids does not influence the plasma magnesium concentration.

OBJECTIVE: Plasma non-esterified (free) fatty acid concentrations rise as a consequence of stimulated endogenous lipolysis and are inversely related to the plasma magnesium concentration when plasma adrenaline concentration is increased. The aim of the study was to test whether high plasma non-esterified fatty acid concentration after infusion of non-esterified fatty acids decreases plasma magnesium concentration. METHODS: Twelve healthy subjects received 500 ml Intralipid or saline in a randomised, cross-over, double-blind design. Infusion of Intralipid results in an isolated elevation of plasma non-esterified fatty acid concentration. Plasma magnesium concentration was determined at baseline and every 30 minutes; plasma non-esterified fatty acid and triglyceride concentrations at baseline and after 120 minutes. RESULTS: Initial plasma magnesium, non-esterified fatty acid, and triglyceride concentrations were similar in both groups. A significant increase in plasma non-esterified fatty acids (2.42 +/- 0.96 mmol/l vs 0.58 +/- 0.23 mmol/l, p = 0.00013) and triglyceride (median and 95th percentile 5.36 (7.35) mmol/l vs 1.18 (1.92) mmol/l, p = 0.003) concentrations was seen with Intralipid. Plasma magnesium concentration increased significantly after Intralipid (0.89 +/- 0.09 mmol/l vs 0.81 +/- 0.06 mmol/l, p = 0.007). No significant changes were seen with saline. A positive association was found between the change in plasma magnesium and triglyceride concentrations (r = 0.85, p = 0.001). CONCLUSION: Acute infusion of non-esterified fatty acids from an exogenous source does not result in a fall in plasma magnesium concentration, indicating that the circulating non-esterified fatty acids play no part in a decrease in plasma magnesium concentration. The high circulating non-esterified fatty acid levels and the fall in plasma magnesium concentration are both a consequence of intracellular lipolysis.

Adult↗
PubMed1997

Tetrahydrobiopterin regulates superoxide and nitric oxide generation by recombinant endothelial nitric oxide synthase.

Nitric oxide (NO) produced by the endothelial isoform of nitric oxide synthase (NOS III) is a key determinant of the anti-atherosclerotic properties of the endothelium. Recent in vivo studies suggest that NOS III may also be a source of superoxide production, which would limit its role as a NO-producing enzyme. In the current study we examined both the NO and the superoxide generating potential of recombinant NOS III obtained from a baculovirus/Sf9 expression system. Using lucigenin chemiluminesence we could indeed demonstrate (superoxide dismutase inhibitable) superoxide production by NOS III. This superoxide production was not affected by administration of L-arginine, but could be inhibited dose-dependently by the co-factor tetrahydrobiopterin (BH4). BH4 also dose dependently decreased superoxide generation by hypoxanthine/xantine oxidase suggesting a direct antioxidant effect. Superoxide generation by NOS III could be completely inhibited by diphenyleneiodonium (DPI), an inhibitor of the flavin moiety of the enzyme, indicating that this group is a main source of superoxide production by the enzyme. Using measurement of [3H-L-arginine] conversion to [3H-L-citrulline], it appeared that BH4 directly increased the production of NO by NOS III. In addition, we observed that BH4 stablized the NOS III in its dimeric form, suggesting that an effect on allosteric conformation could be involved in this effect on NO production. NOS III thus appears to be a superoxide generating enzyme probably through its flavin moiety, as well as a BH4-dependent NO producing enzyme.

Animals↗
PubMed1997

Effect of sodium fluoride on the prevention of corticosteroid-induced osteoporosis.

To investigate whether sodium fluoride (NaF) is able to prevent bone loss in patients treated with corticosteroids (Cs), we performed a randomized double-masked, placebo-controlled trial with 44 Cs-treated patients without established osteoporosis, defined as the absence of previous peripheral fractures and vertebral deformities on radiographs. The effects of NaF (25 mg twice daily) and placebo on the bone mineral density (BMD) of the lumbar spine and hips were compared at baseline and at 6, 12, 18 and 24 months. After 2 years, the BMD of the lumbar spine had decreased in the placebo group by 3.0% (95% CI: -4.9% to -1.0%; p < 0.01); in the NaF group there was a statistically insignificant increase in BMD of 2.2% (95% CI: -0.8% to +5.3%). The difference in the changes in BMD between the two groups was +5.2% (95% CI: +1.8% to +8.6%; p < 0.01). In the hips, BMD had decreased after 2 years in both groups: in the placebo group by -3.0% (95% CI: -5.0% to -1.0%; p < 0.05) and in the NaF group by 3.8% (95% CI: -6.1% to -1.5%; p < 0.01). The difference in the changes in BMD between the two groups was not significant: +0.8% (95% CI: -2.1% to +3.8%). Three vertebral deformities were observed in the placebo group and one in the NaF group (insignificant difference), while no peripheral fractures occurred during the study period. It is concluded that in Cs-treated patients without established osteoporosis NaF prevents bone loss in the lumbar spine but does not have a positive effect on the BMD of the hips.

Adrenal Cortex Hormones↗
PubMed1997

Is addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticosteroid induced osteoporosis?

OBJECTIVE: To investigate whether administration of sodium fluoride (NaF) in addition to cyclical etidronate has a positive effect on bone mineral density (BMD) in patients with established osteoporosis during continued treatment with corticosteroids. PATIENTS AND METHODS: 47 patients who were receiving treatment with corticosteroids were included in a two year randomised, double blind, placebo controlled trial. Established osteoporosis was defined as a history of a peripheral fracture or a vertebral deformity, or both, on a radiograph. All patients were treated with cyclical etidronate, calcium, and either NaF (25 twice daily) or placebo. Vitamin D was supplemented in the case of a low serum 25 (OH) vitamin D concentration. BMD of the lumbar spine and hips was measured at baseline and at 6, 12, 18, and 24 months. RESULTS: After two years of treatment, the BMD of the lumbar spine in the etidronate/NaF group had increased by +9.3% (95% confidence intervals (CI): +2.3% to +16.2%, p < 0.01), while the BMD in the etidronate/placebo group was unchanged: +0.3% (95% CI: -2.2% to +2.8%). The difference in the change in BMD between groups was +8.9% (95% CI: +1.9% to +16.0%, p < 0.01). For the hips, no significant changes in BMD were observed in the etidronate/NaF group after two years: -2.5% (95% CI: -6.8% to +1.8%); in the etidronate/placebo group BMD had significantly decreased: -4.0% (95% CI: -6.6% to -1.4%; p < 0.01). The difference between the groups was not significant: +1.5% (95% CI: -3.4% to +6.4%). No significant differences in number of vertebral deformities and peripheral fractures were observed between the two groups. CONCLUSION: The effect of combination treatment with NaF and etidronate on the BMD of the lumbar spine in corticosteroid treated patients with established osteoporosis is superior to that of etidronate alone.

Adult↗