Biomedical subjects

G Bondjers

Publications and source records attributed to G Bondjers.

At least 37 records · Page 2Linked to original sources

PubMed1996

Binding of human phospholipase A2 type II to proteoglycans. Differential effect of glycosaminoglycans on enzyme activity.

Phospholipase A2 acting on low density lipoproteins in the extracellular arterial intima may form proinflammatory lipid mediators. Human nonpancreatic secretory phospholipase A2 has three regions that may associate with sulfated glycosaminoglycans. The apoB-100 molecule in low density lipoproteins also has glycosaminoglycan binding regions that could mediate its retention in the arterial intima. Here we report that human nonpancreatic phospholipase A2 isolated from a transfected cell line binds to glycosaminoglycans secreted by cultured human arterial smooth muscle cells. A gel mobility shift assay showed that the affinity of phospholipase A2 for glycosaminoglycans from a heparan sulfate/chondroitin sulfate proteoglycan was higher than for chondroitin sulfate glycosaminoglycans from a larger versican-like proteoglycan. Affinity chromatography confirmed these results. All glycosaminoglycans tested, at concentrations up to 100 microM, increased the activity of phospholipase A2 toward phosphatidylcholine liposomes. Above this concentration, heparan sulfate and heparin inhibited the enzyme. Heparin and chondroitin 6-sulfate increased phospholipase A2 activity on low density lipoproteins up to 4-fold at 100 microM, whereas heparan sulfate had no effect. The results indicate that human nonpancreatic secretory phospholipase A2 interacts with proteoglycans via their glycosaminoglycan moiety and that the enzyme activity may be modulated by the association of the enzyme and its substrate to the sulfated polysaccharides.

Chondroitin Sulfates↗

PubMed1996

Alternative splicing determines the binding of platelet-derived growth factor (PDGF-AA) to glycosaminoglycans.

We have shown previously that the platelet-derived growth factor (PDGF) and a synthetic oligopeptide, corresponding to the basic carboxyl-terminal amino acid extension of the long PDGF-A isoform, bind to heparin. Here, we have expressed the long (rA125) and the short (rA109) variants of PDGF A-chains in Escherichia coli and produced the functional homodimers. Surface plasmon resonance analyses showed that while the dimeric rA125 bound with high affinity to low molecular weight heparin, the rA109, lacking the basic extension, did not. This strongly indicated that high affinity binding is due to the carboxyl-terminal extension. Investigations of kinetics and thermodynamics suggested an allosteric binding mechanism. Thus, dimeric rA125 contains two equivalent binding sites. Following low affinity binding of heparin to one binding site, the dimer undergoes a conformational change, increasing the affinity for heparin about 40 times. This positive cooperativity requires the basic amino acid extension in both monomers of the dimeric PDGF molecule. Thermodynamics of the reaction, showing an entropy-driven endothermic process, suggest the involvement of hydrophobic interactions in this rearrangement. Three amino acids in the basic carboxyl-terminal extension were essential for the interaction: the basic residues Arg111 and Lys116, and the polar Thr125. We also found that other glycosaminoglycan species, corresponding to those produced by human arterial smooth muscle cells, bound to dimeric rA125 and that heparan sulfate showed the highest affinity.

Alternative Splicing↗

PubMed1996

Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages.

A large body of evidence suggests that oxidized LDL (oxLDL) has a role in atherogenesis. One effect is the impact on macrophage function. We have studied the effects of oxLDL and oxysterols on the binding of the transcription factors nuclear factor (NF)-kappaB and AP-1 to DNA. These transcription factors are involved in the regulation of several genes and expressed during activation of macrophages, for example by endotoxin (LPS). OxLDL did not induce binding of NF-kappaB. However, the LPS-induced response to NF-kappaB was substantially reduced after preincubation with oxLDL. Medium and highly oxidized LDL also decreased the constitutive DNA-binding of AP-1. Similar effects on AP-1-binding were seen with the oxysterols, 7beta-hydroxycholesterol, 24- hydroxy-, 25-hydroxy-, and 27-hydroxy-cholesterol. Our data therefore suggest an effect of oxLDL on the DNA-binding of AP-1, which might be mediated by the oxysterol content of oxLDL. A decreased LPS-induced TNF-alpha and IL-1beta mRNA and protein expression were found in macrophages incubated with oxLDL before LPS-exposure. These observations suggest that macrophages that internalize extensively oxidized LDL are suppressed in their response to inflammatory stimulation.

Base Sequence↗

PubMed1996

Oxysterols present in atherosclerotic tissue decrease the expression of lipoprotein lipase messenger RNA in human monocyte-derived macrophages.

The presence of oxysterols in macrophages isolated from atherosclerotic tissue and the effect of oxysterols on the regulation of lipoprotein lipase (LPL) mRNA were studied. Both rabbit and human macrophages, freshly isolated from atherosclerotic aorta, show about the same distribution of oxysterols, analyzed by isotope dilution mass spectrometry, except that all three preparations of human arterial-derived macrophages contained high levels of 27-hydroxycholesterol, which was not found in rabbit macrophages. To determine if oxysterols regulate LPL expression, human monocyte-derived macrophages were incubated with different oxysterols. Incubation with 7 beta-hydroxycholesterol and 25-hydroxycholesterol resulted in a 70-75% reduction of LPL mRNA, analyzed by quantitative RT-PCR. Cholesterol and other tested oxysterols showed no effect on macrophage LPL mRNA expression compared with control. LPL activity in the medium was also reduced after exposure of the macrophages to 7 beta-hydroxycholesterol and 25-hydroxycholesterol. In conclusion, we have demonstrated accumulation of oxysterols in macrophage-derived foam cells isolated from atherosclerotic aorta. There was suppression of LPL mRNA in human monocyte-derived macrophages after incubation with 7 beta-hydroxycholesterol and 25-hydroxycholesterol. It is tempting to suggest that an exposure to oxysterols may explain our earlier observation of a low level of LPL mRNA in arterial foam cells.

Animals↗

PubMed1996

Insoluble complex formation between LDL and arterial proteoglycans in relation to serum lipid levels and effects of lipid lowering drugs.

Lipoprotein deposition and increased intimal proteoglycans are characteristics of the atherosclerotic lesion in which low density lipoproteins (LDL) bind with high affinity to proteoglycans. The affinity of LDL to proteoglycans is dependent on its structural and compositional characteristics. This study investigated the relationship between serum lipid levels and LDL-proteoglycan reactivity. We also analyzed how lipid-lowering drugs affect this interaction. Patients with moderate hypercholesterolemia (n = 147) were randomized to pravastatin 40 mg o.d., gemfibrozil 600 mg b.i.d., gemfibrozil+pravastatin (same doses) or placebo. LDL reactivity with proteoglycans was analyzed by precipitation of serum with isolated human arterial proteoglycans. Reactivity was determined as amount of precipitated cholesterol or apolipoprotein (apo) B. Under the conditions used, 53% of the LDL cholesterol and 29% of serum apo B were precipitated. There were strong correlations between precipitated LDL and serum levels of cholesterol, LDL or apo B. No correlations were found with serum lipoprotein(a) (Lp(a)) levels. During pravastatin treatment, cholesterol was reduced by 26.5% and triglycerides by 9.8%. During gemfibrozil treatment corresponding figures were 16.8 and 40.2, and for the combined treatment, 27.5% and 34.2%. On all treatments, the reactivity of LDL with proteoglycan was reduced. The effects were significantly larger in the groups treated with gemfibrozil. This was correlated with the increase in high density lipoprotein (HDL) during gemfibrozil treatment. In hypercholesterolemia, the reactivity of LDL with proteoglycan is increased; treatment with lipid-lowering drugs lowers this reactivity, the effect being greatest for gemfibrozil. This might be due to conformational changes of LDL during treatment with gemfibrozil, unrelated to its lipid lowering effect. Since binding of LDL to proteoglycans is central in atherogenesis, this may be of importance for the role of gemfibrozil as an antiatherogenic drug.

Adult↗

PubMed1996

Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system.

A large proportion of a dense subfraction of LDL in plasma is coupled with an increased risk of coronary artery disease, CAD. This may reflect an increased inflow of such LDL subfractions into the intima, since the inflow of lipoproteins is supposed to be inversely related to the size of the particles. In order to evaluate this possibility we used an in vitro perfusion system for aortic intima-media from rabbits with experimental atherosclerosis. The uptake of human VLDL, LDL, HDL and subfractions of LDL (LDL1, 1.019-1.035 and LDL2, 1.035-1.063 g/ml) in lesions and non-involved areas was studied. Our results indicate that particle size is an important factor for the clearance of lipoproteins into the arterial tissue, both for plaques (VLDL 7.6, LDL 25, HDL 58 nl/mg wet wt./h) and in other areas (VLDL 3.8, LDL 4.1, HDL 12 nl/mg wet wt./h). Interestingly, the uptake of LDL2 was as much as 1.5-1.9 times higher than LDL1. This supports the view that an increased lipid load in the arterial wall may be one mechanism behind the association between denser LDL and CAD. Our data also suggest that the difference between LDL uptake in plaque (576 nl/mg wet wt.) and other areas (48 nl/mg wet wt.) not only reflects a rapid clearance but a large distribution volume of the intima (plaque > 60%, non-involved areas 5.7%).

Animals↗

PubMed1996

Endothelial injury in vivo: a technical and statistical approach to the study of aortic integrity.

The endothelium can be a link connecting risk factors with the development of cardiovascular disease, and methods for studying endothelial integrity are therefore important. We describe a method of studying endothelial injury in vivo by combining immunohistochemistry with an improved technique of producing "enface" preparations (Häutchens) aortic endothelium of rabbits and guinea pigs. These Häutchens enabled the study of large numbers of endothelial cells and adherent cells (probably leukocytes) at different locations along the aorta. The statistical distributions of the number of injured endothelial cells and adherent cells in a visual field were also investigated, and both closely followed a log-normal distribution. Based on this distribution, a method to estimate endothelial injury by grouping the cell count data, instead of exact counting, was developed. The grouped cell count data were then used to calculate the grouped mean and grouped standard deviation for each animal. The improvements of the technical and statistical methods offer good opportunities to study various aspects of endothelial integrity in a time efficient manner.

Animals↗

PubMed1995

Binding of platelet-derived growth factor and low density lipoproteins to glycosaminoglycan species produced by human arterial smooth muscle cells.

The platelet-derived growth factor (PDGF) binds via a defined amino acid sequence to heparin (Fager et al., 1992, In Vitro Cell. Dev. Biol., 28A:176-180) and the protein moiety of low density lipoproteins (LDL; apo B-100) via a similar sequence to chondroitin sulfate (Camejo et al., 1988, Arteriosclerosis Thromb., 8:368-377). In this study, synthetic oligopeptides were used to explore the capacity of smooth muscle cell-derived glycosaminoglycans to bind to the critical sequences of PDGF and apo B-100. In vitro, proliferating human arterial smooth muscle cells synthesized twice as much proteoglycans as did quiescent cells. The dominating glycosaminoglycan side chains were chondroitin and heparan sulfates in secreted and cell-associated proteoglycans, respectively. The chondroitin sulfate-rich proteoglycans had a higher molecular size and were to a larger extent secreted into the culture medium than the heparan and dermatan sulfate-rich proteoglycans. Heparan, dermatan, and chondroitin sulfates bound to the PDGF-derived oligopeptide with affinities similar to those of heparin. However, while heparan and dermatan sulfates both inhibited DNA synthesis in human arterial smooth muscle cells, chondroitin sulfate had no such inhibitory effect. Like the PDGF-derived oligopeptide, the apo B-100-derived oligopeptide bound to these glycosaminoglycans. At the same time, both oligopeptides displaced bound LDL from chondroitin sulfate in vitro and released the block on DNA synthesis in smooth muscle cells that heparin induced in culture. Thus, chondroitin, dermatan, and heparan sulfates produced by arterial smooth muscle cells may bind LDL and PDGF competitively in atherogenesis but only heparan and dermatan sulfates inhibit cellular DNA synthesis. LDL and PDGF deposition may occur by binding to similar binding sites on glycosaminoglycans derived from smooth muscle cells within atherosclerotic lesions.

Apolipoprotein B-100↗

PubMed1995

Effects of injury on apoB kinetics and concentration in rabbit aorta.

Endothelial injury or dysfunction and deposition of lipoproteins and cholesterol are key events during the development of atherosclerosis. We have studied the lipoprotein kinetics in arterial tissue in relation to endothelial injury and re-endothelialization. Endothelial injury was induced in rabbits by use of a balloon catheter. With a specific immunoradiometric assay, apoB levels in arterial tissue were measured at different time points for up to 10 weeks after injury. Forty-five minutes before being killed, the rabbits were injected with 125I-LDL, and influx of LDL was calculated from the accumulation of radioactivity in the arterial tissue. The concentration of apoB in the injured arterial tissue was four times higher than that in control arterial tissue (P < .0001). Within the lesion the concentration was as high in nonendothelialized as in re-endothelialized regions. The tissue pool of apoB was divided into a loosely bound fraction and a tightly bound fraction. The increase of apoB in the injured areas was primarily due to an increase in the tightly bound fraction. The influx of apoB was severalfold higher in nonendothelialized tissue than in re-endothelialized tissue or control areas (P < .005). When retention time was calculated, this was found to dramatically increase (by seven times) the tightly bound pool of apoB in the re-endothelialized areas. In addition to the large increase of a tightly bound apoB pool in injured areas, we found a prolonged retention time of apoB in the lesions, but only in the re-endothelialized areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Interferon gamma binds to extracellular matrix chondroitin-sulfate proteoglycans, thus enhancing its cellular response.

The amino acid sequence of interferon gamma (IFN-gamma) has basic amino acid clusters similar to the heparin-binding consensus sequences found in other proteins that bind to proteoglycans (PGs). We investigated whether recombinant human IFN-gamma could bind to extracellular matrix (ECM) PGs secreted by human arterial smooth muscle cells (HASMCs) in vitro and whether the interaction affected the cellular response to IFN-gamma. As an in vitro model of ECM we used the basement membrane from HASMCs in culture. The binding of 125I-IFN-gamma to ECM was reduced significantly by pretreatment of ECM with chondroitinase ABC, an enzyme that degrades chondroitin-sulfate glycosaminoglycans. IFN-gamma binding to ECM was reduced by increasing concentrations of chondroitin-6-sulfate. 125I-IFN-gamma (0.05 to 2 ng/mL) binding data indicated an apparent Kd of 2 x 10(-11) mol/L and a maximum binding of 1.6 x 10(6) IFN-gamma molecules bound per square millimeter of ECM. Experiments with synthetic peptides suggested that residues 127 through 135 (AKTGKRKRS) are involved in the binding. The binding to chondroitin-sulfate PGs was confirmed by affinity chromatography of isolated [35S]chondroitin-sulfate PGs from ECM and cell-culture medium on immobilized IFN-gamma. The binding was abolished by treatment with chondroitinase ABC. ECM-bound IFN-gamma was more effective in inducing the expression of class II major histocompatibility antigens such as HLA-DR in HASMCs and human arterial endothelial cells than soluble IFN-gamma. These results suggest a role for chondroitin-sulfate PGs in immobilizing IFN-gamma in the ECM compartment and enhancing the cellular response to IFN-gamma.

Amino Acid Sequence↗

PubMed1994

Measurement of antioxidant activity in lipoproteins using enhanced chemiluminescence.

We describe a new assay for antioxidant activity (AOA) in lipoprotein solutions based upon their potential to quench light emission from a glowing horseradish peroxidase-catalyzed enhanced chemiluminescent reaction. By comparison with the quenching activity of the tocopherol-analogue trolox the AOA can be quantified. These measurements suggest that all lipoprotein fractions have significant AOA and that this has a non-linear relationship with lipoprotein concentration increasing significantly on a per particle basis at higher concentrations. Mean AOA in very low density, low density and high density lipoprotein fractions were 39.9 +/- 5.3, 20.3 +/- 4.0 and 5.3 +/- 1.0 mumol of trolox equivalents per litre, respectively, when measured at 1 mg protein/ml. Using known values for the protein content of the lipoprotein fractions, these values correspond to 79.8 +/- 10.7, 10.3 +/- 2.0 and 0.84 +/- 0.15 equivalents per particle. Parallel measurements of light emission and conjugated diene formation suggest that the oxidative stress imposed by the peroxidase-catalyzed reaction leads to lipid peroxidation but only after all AOA has been exhausted. AOA was significantly correlated with the alpha-tocopherol content in 30 lipoprotein samples (r = 0.764). This assay offers a rapid and simple method for investigating the effects of diseases, drugs or dietary manipulation on lipoprotein AOA.

Antioxidants↗

PubMed1994

Anti-atherosclerotic effects of beta-blockers.

Mechanisms involved in the development of atherosclerosis are reviewed. Based primarily on experimental studies, the following key steps are suggested; (1) endothelial injury; (2) platelet and leukocyte adhesion; (3) smooth muscle proliferation; (4) lipid deposition; (5) arterial tissue hypoxia. Beta-blockers may interfere with (1), (2), (4) and (5), and have been shown to inhibit experimental atherosclerosis, even if given after the disease has been established. Calcium channel and ACE inhibitors interfere with (2), and have been shown to inhibit experimental atherosclerosis if given throughout the experimental period. It is unclear whether the association between hypertension and atherosclerosis is causal. Therefore, antihypertensive agents should be selected according to their potential to interfere with the atherosclerotic process. The primary choice would then be beta-blockers, combined with calcium channel or ACE inhibitors if the patient is considered to be at risk of developing new lesions.

Adrenergic beta-Antagonists↗

PubMed1994

Serum triglycerides and HDL cholesterol--major predictors of long-term survival after coronary surgery.

The influence of pre-operative serum lipid levels on late clinical outcome after coronary artery bypass surgery was analysed in 83 patients undergoing coronary bypass surgery for stable angina pectoris. The mean follow-up period for surviving patients was 105 +/- 33 months (range 65-133). Twenty-two patients (27%) had died during follow-up, of whom 14 had sustained a fatal myocardial infarction and four had succumbed to other cardiovascular causes. Thirty-one patients sustained 35 cardiac events, defined as either fatal or non-fatal myocardial infarction, or reoperation, or PTCA during the follow-up period. With univariate analysis, pre-operative serum levels of total cholesterol and triglycerides were significantly related to cardiac events, P < 0.05 and P < 0.05, respectively. In a Cox proportional analysis, cardiac mortality and total mortality were related to serum triglycerides and HDL cholesterol (P < 0.05 and P < 0.01 respectively). Eighty-five percent of the patients with triglycerides < 2.0 mM.l-1 survived for 10 years, while only 48% of patients with triglycerides > 2.0 mM.l-1 remained alive for that period. Figures were similar for subjects with HDL cholesterol > 1.0 mM.l-1 or HDL cholesterol < 1.0 mM.l-1, at 89 and 38%, respectively. Only 28% of the patients with the combination triglycerides > 2.0 mM.l-1 and HDL cholesterol < 1.0 mM.l-1 were alive 10 years after surgery. These data suggest that dyslipidaemia, especially the combination of high serum triglycerides and low HDL cholesterol, is an important factor influencing long-term clinical outcome after coronary bypass surgery.

Angina Pectoris↗

PubMed1994

Lipoprotein fractionation in deuterium oxide gradients: a procedure for evaluation of antioxidant binding and susceptibility to oxidation.

Oxidative modifications of lipoproteins appear to contribute to their atherogenicity. Very low and low density lipoproteins (VLDL and LDL) are protected against these modifications by antioxidants that can be incorporated in vivo or in vitro into the particles. We describe here ultracentrifugal procedures for isolation of VLDL and LDL that do not require subsequent dialysis or buffer equilibration. Lipoproteins were isolated in buffers with physiological ionic composition prepared in D2O (deuterium oxide). This allowed measurements of the content of antioxidants and of the susceptibility to oxidation of the isolated LDL without further manipulations. Conventional ultracentrifugal methods use high salt concentrations and require additional steps to eliminate them. This introduces uncertainties in the evaluation of antioxidant binding and on measurements of their effect on VLDL and LDL oxidation. With the method described, the composition of the isolated VLDL and LDL was indistinguishable from that of fractions isolated with KBr gradients. Also, the content of alpha-tocopherol was similar. LDL isolated with KBr solutions appeared to bind 20-45% more of the probucol present in serum than LDL isolated in isotonic solutions prepared with D2O. This was the case with probucol incorporated into plasma or serum in vivo or in vitro. Five out of seven LDL isolated with the D2O procedure from different human sera appeared more resistant to Cu(2+)-catalyzed oxidation than those obtained with KBr gradients from the same serum. In addition to the gradient procedure, we also describe a preparative version of the method that can be used with multiple samples.

Animals↗

PubMed1993

Binding of low density lipoproteins by proteoglycans synthesized by proliferating and quiescent human arterial smooth muscle cells.

Chondroitin sulfate-rich proteoglycans secreted by arterial intima smooth muscle cells appear involved in low density lipoprotein entrapment and modification. Hypothetically, such a process may contribute to atherogenesis. We compared composition and size of those proteoglycans synthesized by proliferating and resting human arterial smooth muscle cells for which low density lipoprotein had affinity. Lipoprotein-binding proteoglycans secreted by proliferating cells were larger than those of resting cells (M(r) = 1.1 x 10(6) versus 0.8 x 10(6). This was primarily caused by increased M(r) of the chondroitin sulfate chains (6 x 10(4) versus 3.5 x 10(4)). The glycosaminoglycan chains of the proteoglycans from both cells were made of more than 90% chondroitin 6-sulfate and chondroitin 4-sulfate in a 6:4 ratio. Affinity chromatography indicated that low density lipoprotein had a higher affinity with the proteoglycans synthesized by proliferating cells than those from resting cells. Measured with gel mobility shift assay, the apparent affinity constant of low density lipoproteins for proteoglycans from proliferating cells was 3-fold higher than that for proteoglycans from resting cells. This increased affinity appeared related to the higher relative proportion of proteoglycans with longer glycosaminoglycan chains secreted by the proliferating cells than those secreted by the resting cells.

Arteries↗

PubMed1993

Binding of a synthetic apolipoprotein B-100 peptide and peptide analogues to chondroitin 6-sulfate: effects of the lipid environment.

The association of apolipoprotein B-100 (apoB-100) containing lipoproteins, low-density lipoproteins (LDL), very low density lipoproteins (VLDL) and lipoprotein(a) [Lp(a)] with chondroitin sulfate-rich proteoglycans (CSPG) of the arterial intima appears to contribute significantly to lipoprotein disposition during atherogenesis. Using frontal elution analysis and competition experiments, we have previously suggested that the apoB-100 segment RLTRKRGLK (3359-3367) is a mediator of the association between LDL and arterial CSPG. Here, with direct binding measurements and fluorescence titrations, we evaluated the effect of the lipid environment on the affinity of the above apoB-100 segment for chondrotin 6-sulfate (C6S). We synthesized a secondary model peptide with hydrophobic tails which allowed its binding to lipid vesicles and lipoproteins (VVWRLTRKRGLKVVV). When associated with lipid vesicles, this peptide showed a higher affinity (KD = 3.9 microM) for C6S than the free peptide (KD = 18.7 microM). However, the affinity was still lower than that of LDL (KD = 0.21 microM). The increase in affinity for the peptide after association with lipid vesicles indicates that the secondary structure induced by its association with lipid vesicles is a significant modulator of the affinity for glycosaminoglycans. When bound to LDL and VLDL subfractions, VVWRLTRKRGLKVVV increased the affinity of the lipoproteins for C6S. The results suggest that, with the proper secondary structure induced by the lipid environment, the segment RLTRKRRGLK of apoB-100 is an important determinant of the association of LDL and VLDL with glycosaminoglycans but that probably other basic segments contribute to this interaction.

Amino Acid Sequence↗

PubMed1993

Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia.

PURPOSE: To compare the efficacy and safety of pravastatin, gemfibrozil, combined therapy, and placebo in the treatment of hypercholesterolemia. PATIENTS AND METHODS: At 5 centers in Sweden and 2 in Finland, 290 ambulatory patients were randomized to active treatment or placebo for 12 weeks following a single-blind placebo lead-in period. The study was double-blind and placebo-controlled. Patients has plasma total cholesterol levels of at least 6.0 mmol/L or in the 90th percentile by age and sex and triglycerides less than 4.0 mmol/L. Concentrations of lipids, lipoproteins, and apolipoproteins were measured, and clinical laboratory tests included liver function and creatine kinase determinations. RESULTS: Pravastatin reduced total cholesterol (26.3% versus 15.2%, p < or = 0.01), low-density lipoprotein cholesterol (LDL-C) (33.5% versus 16.8%, p < or = 0.01), and apolipoprotein B (28.8% versus 15.3%, p < or = 0.01) more than gemfibrozil. Gemfibrozil reduced very-low-density lipoprotein cholesterol (VLDL-C) (49.1% versus 21.9%, p < or = 0.01) and triglycerides (42.2% versus 14.2%, p < or = 0.01) and increased high-density lipoprotein cholesterol (HDL-C) (15.2% versus 5.9%, p < or = 0.01) more than pravastatin. Pravastatin and gemfibrozil increased apolipoprotein A-I comparably (3.3% versus 5.0%, p = NS). The combination significantly (p < or = 0.01) reduced total cholesterol (29.0%), LDL-C (37.1%), VLDL-C (49.4%), and apolipoprotein B (31.6%), and increased HDL-C (16.8%). The combination reduced the total cholesterol/HDL-C (39.3%) and LDL-C/HDL-C (45.8%) ratios significantly (p < 0.01). Adverse events and clinical laboratory abnormalities were generally mild and transient in all groups, although creatine kinase tended to be higher with combination therapy. Study drugs were withdrawn from two patients with asymptomatic creatine kinase elevations. Severe myopathy was not observed; however, the presence of subclinical musculoskeletal effects cannot be excluded. CONCLUSIONS: Co-administration of pravastatin and gemfibrozil combined the specific effects of the two drugs on lipoprotein concentrations and ratios. The incidence of side effects was low; severe myopathy did not occur. The combination may be useful in selected cases of combined hyperlipidemia; however, since myopathy at a low incidence or after long-term therapy cannot be excluded, the routine use of combination therapy is not advisable.

Adult↗

PubMed1993

Apolipoprotein E phenotypes in familial hypercholesterolaemia: importance for expression of disease and response to therapy.

To study the possible importance of variation at the apolipoprotein (apo) E gene locus for the clinical expression of heterozygous familial hypercholesterolaemia (FH), we determined apo E phenotype and serum lipoprotein pattern in 120 patients with FH. The allele frequency of the patients studies were: epsilon 2 0.033, epsilon 3 0.733, and epsilon 4 0.233. There was no influence of apo E phenotype on the serum concentrations of total. VLDL, LDL or HDL cholesterol, triglycerides, or of apo AI, B or (a). Serum concentrations of apo E were significantly higher in patients with the apo E 3/3 phenotype compared to those with apo E 4/3 or 4/4, and the highest concentrations were found in patients carrying the epsilon 2-allele. The cholesterol-lowering response to therapy with cholestyramine or pravastatin was not related to apo E phenotype. It is concluded that variation at the apo E gene locus is not of major importance for the expression of heterozygous FH.

Apolipoproteins E↗