Elsevier

Atherosclerosis

Volume 126, Issue 2, 25 October 1996, Pages 305-312
Atherosclerosis

Decreased susceptibility of low-density lipoproteins to in-vitro oxidation after dextran-sulfate LDL-apheresis treatment

https://doi.org/10.1016/0021-9150(96)05919-9Get rights and content

Abstract

Low-density lipoproteins (LDL)-apheresis is a well established treatment of severe hypercholesterolemia resulting in fast clinical improvement and angiographically proven regression after 6 months of therapy. The underlying mechanisms, beside lipoprotein removal, are still under debate. Recently, oxidized LDL were shown to be of key importance in foam cell formation and atherosclerotic lesion development. We examined the influence of dextran-sulfate LDL-apheresis on the susceptibility of LDL to oxidation in 6 patients (5 males, 1 female, age: 41–60 years) suffering from severe heterozygous hypercholesterolemia or combined hyperlipidemia. LDL-apheresis influenced the oxidizability of LDL by a significant (P < 0.01) prolongation of the median of lag time (min) for LDL samples (before treatment 75, range: 31–176 versus after treatment 129.5, range 45–286). A significant (P < 0.01) difference could be also observed in the amount of conjugated dienes as expressed by the maximum rate in absorbance (before treatment 15.39, range: 5.29–21.22 versus after treatment 20.20, range 12.88–72.33). Thiobarbituric acid reactive substances (TBARS) formation was significantly decreased in LDL obtained after apheresis treatment as compared to pretreatment LDL. Electrophoretic mobility (EM) of LDL obtained before and after LDL-apheresis revealed a significant increase (P < 0.05) from a mean of 8.8 ± 0.5 to a mean of 10.5 ± 0.5 mm. The titers of plasma autoantibodies against oxLDL (oLAb) which varied considerably interindividually, were not influenced by LDL-apheresis treatment. Levels of F2-isoprostanes, as measured by plasma levels of 8-iso-prostaglandin-F (8-iso-PGF), reflecting oxidative stress, did not change, either. In summary, our findings provide evidence that even one single dextran sulfate LDL-apheresis treatment decreases LDL-oxidizability, which is an additional beneficial effect to that of lipid lowering.

Introduction

Low-density lipoproteins (LDL) are known to be a major risk factor for the development of atherosclerosis [1]. LDL, the main carriers of cholesterol in the blood stream, were shown to accumulate within the arterial wall. It is well established that increased levels of LDL cause an increased risk for atherosclerosis [2] and therapeutic intervention against hypercholesterolemia has been shown to retard or stop the progression of atherosclerosis. LDL in their modified or oxidized form are not recognized by the LDL-receptor, but are taken up by the arterial wall cells, especially by macrophages, in a non-regulated manner through the so-called scavenger-receptor pathway. This process leads to the formation of foam cells, the hallmark of the atherosclerotic lesion. Oxidized LDL have been shown to be present in human lesions [3] and antioxidants have been demonstrated to reduce lesion formation [4]. LDL-oxidation generates molecular epitopes with antigenic properties. It has been shown that autoantibodies against oxidized LDL epitopes, namely malondialdehyde (MDA)-lysine residues, are formed in vivo. Increased titres of serum autoantibodies were observed in patients at risk for atherosclerosis [5], with progressive carotid atherosclerosis [6], essential hypertension [7] or with kidney failure with conservative therapy or hemo- or peritoneal dialysis [8].

Recently, it was reported that prostaglandin-like compounds (F2-isoprostanes) were produced in vivo by non-enzymatic peroxidation of arachidonic acid [9]. These compounds, which are known to be potent cellular mitogens and vaso-constrictors, are also released during in vitro copper-induced oxidation of LDL [10]. They have been claimed to be useful markers for oxidant injury. For example, F2-isoprostanes were found to be significantly elevated in plasma of rats during perfusion after hepatic ischemia [11] and in patients with the hepatorenal syndrome [12]. It is suggested that the release of F2-isoprostanes from oxidized LDL is indicative for the degree of oxidative stress and could also contribute to the development of atherosclerosis.

LDL-apheresis is a safe and efficacious intervention not only to normalize lipids and lipoproteins, but also to improve blood rheology. LDL-apheresis retards the progression and even regresses advanced lesions in patients with severe familial hypercholesterolemia (FH) which appears in its heterozygous form with a prevalence of 1 in 500, in its homozygous form in 1 in 1 000 000. Dietary and pharmacological interventions, even combined, are sometimes insufficient to reach the recommended values for secondary prevention. Thus, LDL-apheresis becomes the treatment of choice in these patients. A concomitant HMG-CoA-reductase inhibitor therapy is necessary to improve the efficacy of the treatment in patients with the heterozygous form of this disease. It has been reported that LDL-apheresis improves the haemorrheological profile [13], as well as platelet function [14], though there are conflicting reports [15]. Rapid improvement of clinical symptoms has been explained by morphological regression of atherosclerotic lesions being observed at the earliest after 6 months of therapy.

Studies on the susceptibility of LDL to oxidation before and after LDL-apheresis have been only published in abstract form [16]. With regard to the well documented role of LDL oxidation in the process of atherosclerosis, it was, therefore, the aim of this study to investigate the influence of LDL-apheresis on LDL oxidizability before and immediately after LDL apheresis.

Section snippets

Subjects and methods

Plasma samples were obtained from 6 patients (5 males, 1 female; 41–60 years old, Table 1) suffering from severe heterozygous familial hypercholesterolemia undergoing biweekly dextrane-sulphate apheresis. LDL-apheresis was performed using dextran sulfate cellulose (Kaneka Kanegafuchi, Osaka, Japan) adsorption. LDL is bound by dextran sulfate in two coupled cellulose columns, each containing 150 ml dextran sulfate cellulose gel. After filling with 0.9% NaCl the system is primed by heparinisation

Continuous monitoring of conjugated dienes

Table 2 shows the oxidation pattern of LDL immediately before and after LDL-apheresis. LDL-apheresis affects the oxidizability of LDL by significant (P < 0.01) prolongation of the lag time for LDL samples obtained after apheresis treatment compared to the samples obtained before apheresis treatment. Fig. 1 demonstrates the differences in lag time before and after LDL-apheresis for each single patient. A significant (P < 0.01) difference could be also observed in the amount of conjugated dienes

Discussion

In this study we investigated the susceptibility to oxidation of LDL obtained from patients undergoing biweekly LDL-apheresis. LDL were isolated from plasma obtained immediately before and after LDL-apheresis treatment. The results show an additional benefit of this treatment of severe hypercholesterolemia (combined hyperlipidemia) by LDL-apheresis. The benefit is a decreased susceptibility of LDL particles to oxidation. This mechanism might contribute to the induction of regression in these

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