Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH

Abstract

Many cholesterol-laden foam cells in atherosclerotic lesions are macrophages and much of their cholesterol is present in their lysosomes and derived from low density lipoprotein (LDL). LDL oxidation has been proposed to be involved in the pathogenesis of atherosclerosis. We have shown previously that LDL can be oxidised in the lysosomes of macrophages. a-Tocopherol has been shown to inhibit LDL oxidation in vitro, but did not protect against cardiovascular disease in large clinical trials. We have therefore investigated the effect of a-tocopherol on LDL oxidation at lysosomal pH (about pH 4.5). LDL was enriched with a-tocopherol by incubating human plasma with a-tocopherol followed by LDL isolation by ultracentrifugation. The a-tocopherol content of LDL was increased from 14.4 ± 0.2 to 24.3 ± 0.3 nmol/mg protein. LDL oxidation was assessed by measuring the formation of conjugated dienes at 234 nm and oxidised lipids (cholesteryl linoleate hydroperoxide and 7-ketocholesterol) by HPLC. As expected, LDL enriched with a-tocopherol was oxidised more slowly than control LDL by Cu 2þ at pH 7.4, but was not protected against oxidation by Cu 2þ or Fe 3þ or a low concentration of Fe 2þ at pH 4.5 (it was sometimes oxidised faster by a-tocopherol with Cu 2þ or Fe 3þ at pH 4.5). a-Tocopherol-enriched LDL reduced Cu 2þ and Fe 3þ into the more pro-oxidant Cu þ and Fe 2þ faster than did control LDL at pH 4.5. These findings might help to explain why the large clinical trials of a-tocopherol did not protect against cardiovascular disease.

Vitamins E and C do not effectively inhibit low density lipoprotein oxidation by ferritin at lysosomal pH

“…Preventing LDL oxidation was considered one of the most impoprtant strategies to reduce cardiovascular diseases, but the large clinical trials of antioxidants, mainly a-tocopherol and ascorbate, showed no protection [6][7][8][9][10]. We previously showed that a-tocopherolenrichment of LDL did not protect LDL effectively against oxidation by ferric iron, copper ions or a low concentration of ferrous iron at lysosomal pH (pH 4.5), but as expected it protected LDL against oxidation by copper at pH 7.4 [20]. In the present study, enrichment of LDL with a-tocopherol did not protect LDL from oxidation by ferritin at lysosomal pH (Figure 1).…”

“…Increasing the a-tocopherol content of LDL has been shown to decrease its oxidisability by macrophages or copper [16,17], but a-tocopherol can increase the oxidation of LDL if the oxidative stress is low because the a-tocopherol radical can abstract a hydrogen atom from a polyunsaturated lipid and promote peroxidation [18,19]. Supplementation of LDL with a-tocopherol does not protect LDL from oxidation by copper or ferric iron or a low concentration of ferrous iron at lysosomal pH [20]. a-Tocopherol has been shown to reduce diet-induced atherosclerosis in rabbits [21,22] and decreased atherosclerotic lesion formation in apoE-deficient mice fed an atherogenic diet [23] and LDL receptor-deficient mice on a low [24] or high fat diet [25], but it sometimes had no effect on atherosclerosis or even increased it [26].…”

Synthesis and evaluation of antioxidant activity of some novel hydroxypyridinone derivatives: a DFT approach for explanation of their radical scavenging activity

“…Polyphenols, e.g . catecholes, can remove Fe 2+ out of reach by chelation and inhibition of Fenton or Haber-Weiss reactions as well as free radical scavenging ( 8 9 ).…”

Vitamin E in Human Health and Oxidative Stress Related Diseases

“…Emerging research outputs are shedding light on the disparity between in vitro and in vivo antioxidant capacity of vitamin E [85]. In macrophages, the oxidation of lipids occur in the lysosomes.…”

“…In macrophages, the oxidation of lipids occur in the lysosomes. Alboaklah and Leake [85] conducted an experiment on LDL oxidation at lysosomal pH (about 4.5). In their experiment, LDL enriched with vitamin E was oxidized by Cu 2+ more slowly compared to control LDL.…”