HDL composition and HDL antioxidant capacity in patients on regular haemodialysis
Introduction
The major cause of death in patients with end-stage renal failure receiving renal replacement therapy is cardiovascular disease [1], [2], [3], [4]. A number of factors contribute to accelerated atherogenesis in the presence of renal failure, including hypertension, diabetes and dyslipidaemia. However, after taking the increased prevalence of conventional risk factors into account, a substantial proportion of the increased cardiovascular risk remains unexplained.
Recent work in relation to atherogenesis has focused on the oxidation of LDL within the arterial wall [5], [6]. LDL oxidation is currently considered to be a key early event in the development of atherosclerosis. The oxidation of polyunsaturated fatty acids within LDL is followed by their breakdown and the release of aldehydes and ketones, such as malondialdehyde and 4-hydroxynonenal, which can modify lysine residues on apolipoprotein B (apo B) [7]. Modified apo B is no longer recognised by the apo B receptor, but instead taken up by the macrophage scavenger receptor. This leads to unregulated uptake of LDL cholesterol and the formation of foam cells, and eventually results in a fatty streak, the first phase of an atherosclerotic lesion [7].
Several factors, such as activation of neutrophils during haemodialysis [8], iron overload [9] and accumulation of advanced glycation endproducts [10], contribute to increased oxidative stress in patients with chronic renal failure. Consequently, lipid peroxidation products are elevated in chronic renal failure [11]. Depletion of antioxidants may further facilitate lipid peroxidation. In patients with chronic renal failure lower levels of α-tocopherol, β-carotene, lycopene and particularly ascorbate are found [9], [11], [12], [13]. Surprisingly, however, the majority of studies assessing the susceptibility of LDL to oxidation in renal failure have suggested that it is not increased [14], [15], [16], [17]. This may be attributable to increased LDL monounsaturated fatty acid content, which increases the resistance of LDL to oxidation [14].
LDL concentrations in chronic renal failure are usually unchanged, whereas decreased HDL levels are a characteristic finding [18]. Epidemiological studies have demonstrated a strong inverse correlation between plasma levels of HDL and cardiovascular risk [19], and patients with chronic renal failure and low HDL appear to be at a particularly high risk [20]. Traditionally, the anti-atherogenic properties of HDL have been attributed to the role of HDL in reverse cholesterol transport; HDL removes excess cholesterol from peripheral tissues and transports it to the liver [21]. More recently, however, it has been shown that HDL can protect LDL against oxidation [22], [23], [24] and inhibit LDL induced monocyte transmigration [25].
Several mechanisms have been suggested which could enable HDL to protect against the oxidation of LDL in vitro. There may be a shift of lipid peroxidation products from LDL to HDL [26], followed by the conversion of cholesteryl ester hydroperoxides to stable cholesteryl ester hydroxides [27]. Alternatively, HDL associated enzymes, such as paraoxonase [28], [29], platelet-activating factor acetylhydrolase (PAF-AH) [30], [31] or lecithin-cholesterol acyltransferase (LCAT) [32] have been shown to inhibit LDL oxidation in vitro and to convert bioactive lipid peroxidation products into inactive compounds.
The aim of our study was therefore to investigate whether compositional changes of HDL in patients with chronic renal failure result in increased intrinsic susceptibility of HDL to oxidation and decreased ability of HDL to inhibit copper-induced oxidation of LDL.
Section snippets
Materials and methods
All chemicals were obtained from Sigma (Dorset, UK) unless otherwise stated.
Results
Lipid profiles, apolipoprotein levels, paraoxonase/arylesterase and PAF-AH activities of patients on haemodialysis and controls are shown in Table 1. HDL concentrations in the patient group were marginally decreased (1.05±0.23 vs. 1.32±0.36 mmol/l, P=0.062). The Apo A-I and apo A-II levels were reduced in patients on haemodialysis: 103.00±33.41 versus 171.65±39.17 mg/100 ml, P<0.01 for apo A-I and 37.17±5.42 versus 48.20±13.57 mg/100 ml, P<0.05 for apo A-II. Arylesterase activity was also
Discussion
There is a strong inverse correlation between HDL cholesterol concentrations and the risk of atherosclerosis [19]. Traditionally, the anti-atherogenic properties of HDL have been attributed to its function in reverse cholesterol transport [21]. Recently, however, it has been shown that HDL has the ability to directly inhibit the metal-dependent oxidation of LDL in vitro [22], [23], [24], [25]. LDL oxidation is believed to be a key early event in the development of atherosclerosis. Patients with
Acknowledgements
We are grateful to the Northern Ireland Chest, Heart and Stroke Association and Deutscher Akademischer Austauschdienst for their support for our work in this area.
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