Title: The oxidative modification of low density lipoproteins
Key words: cardiovascular disease, lipid metabolism, cholesterol, lipoproteins, abnormal lipid, dietary manipulation, antioxidant, atherosclerosis, LDL, low density lipoprotein, HDL, high density lipoprotein, oxidative modification, macrophages, intima, foam, endothelial, adhesion, cytotoxic, nitric oxide, plaque, protein kinase C, vasodilation, superoxide, radicals, thrombosis, trans fatty acid, folic acid, vitamins, vitamin A, vitamin C, vitamin B12, vitamin B6, homocysteine, fibrinolytic,
Date: Sept 2006
Author: Morgan, G
The oxidative modification of low density lipoproteins
The hypothesis that cardiovascular disease represents a local and general dysfunction of lipid metabolism is now widely accepted. Studies such as the Seven Countries Study (Keys 1980) and later work (Burr 1989, Riemersma 1992) showed both elevated levels of cholesterol and lipoproteins in cardiovascular disease but also an abnormal lipid profile. It was shown that modification of this profile by dietary means could be achieved with beneficial results (Ramirez 1980, Lichtenstein 1999).
Other work (Gey 1991) identified an inverse relation between antioxidant levels and cardiovascular disease and the beneficial results of intervention supplementation trials (Stampfer 1993, Rimm 1993, CHAOS study 1996). The body of this evidence led to the hypothesis (Steinberg 1989) that the major mechanism at work in the pathogenesis of atherosclerosis in man was the oxidative modification of low density lipoprotein (LDL). More recent research has led to modifications to this hypothesis and will be reviewed here.
Steinberg’s model described the unregulated fixing of oxidised LDL (oxLDL) by ‘scavenger’ LDL receptors (Brown 1983). The chemotactic properties of oxLDL leads to endothelial adhesion of monocytes to the endothelium and their tranformation into foam-containing macrophages in the intima. The cytotoxic nature of oxLDL leads to both endothelial and other tissue damage. The release of proteases and necrotising material leads to the formation of fatty streaks, smooth muscle cell proliferation and the pathological features of atherosclerosis (Folk 1992).
Research has shown oxLDL to be present in atherosclerotic lesions (Yla- Herttuala 1989) and to be associated with oxLDL antibodies whose distribution and level mirrors the atherosclerotic process (Salonen 1992). Antioxidants such as vitamin E are able to prevent oxidation of LDL and are able to stem the progression of the disease (Parthasarathy 1986). OxLDL has also been shown to inactivate nitric oxide which promotes vasodilation and prevents smooth muscle cell migration and platelet aggregation (Chin 1992). Although one study (Hodis 1995) showed reduction in the rate of progression of coronary artery disease with vitamin E supplementation, most studies (Kleinveld 1992, CHAOS 1996) have shown no radiographic or pathological evidence demonstrating the benefit of antioxidants. The diminished mortality rate demonstrating the efficacy of such interventions has led some workers to suppose that plaque stability, involving pathways other than those associated with oxLDL, might be involved.
Significant atherosclerosis is known to be present in childhood in developed countries (Stany 1983) and the assumption is that these factors could be operative in the adult age group. One such factor is protein kinase C. Inhibition by vitamin E of this enzyme leads to the promotion of nitric oxide release and vasodilation (Kugiyama 1990), decreased monocyte adhesion (Devaraj 1996 ), inhibition of smooth muscle cell proliferation (Boscoboinik 1991) and diminished platelet aggregation (Freedman 1996). Vitamin C has been shown to produce vasodilation, perhaps by acting as a scavenger for superoxide radicals (Levine 1996).
Dislocation of transition metal ions has also been postulated as a cause of non-oxLDL mediated atherosclerosis. The zinc/copper hypothesis (Klevay 1975) states that zinc/copper superoxide dismutase- mediated oxidation is an important factor. Low copper levels also lead to depression of nitric oxide synthesis (Dicks 1996) with migration of smooth muscle cells, apoptosis and vasoconstriction (Sarkar 1996, Lamb 2002). These studies support the idea that plaque stability, vasomotor function and the tendency to thrombosis are subject to modification by alternative antioxidant pathways, many modulated by nitric oxide (Bult 1999).
Other factors, genetic and dietary, determine the evolution of atherosclosis. Lipoprotein(a), a significant factor in atherogenesis, is largely determined by phenotypic expression but also by dietary factors (Brown 1993). Increased consumption of trans fatty acids (Lichtenstein 1999, Ascherio 1999) and reduced levels of folic acid and vitamins B6 and B12 (Peterson 1998) are associated with elevated homocysteine levels leading to the formation of complexes with lipoprotein(a) and oxidative and fibrinolytic changes associated with increased atherosclerosis( Lang 2000,Foody 2000).
It is clear from this more recent research that atherogenesis is multifactorial and involves many other pathways than that of LDL oxidation. In the light of this information revision of Steinberg’s original oxidative hypothesis appears in order.
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