Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: A possible explanation as to why the clinical trials of antioxidants might have failed

Ahmad, Feroz; Leake, David S.

doi:10.1016/j.chemphyslip.2018.03.001

Cited by 21 publications

(29 citation statements)

References 52 publications

(75 reference statements)

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“…DPPD effectively inhibits oxidation of LDL by copper and endothelial cells at pH 7.4 (Sparrow et al, 1992) and by ferrous iron at pH 4.5 (Ahmad and Leake, 2018). It also protects against atherosclerosis in cholesterol-fed rabbits (Sparrow et al, 1992) and decreases atherosclerosis in apoE deficient mice (Tangirala et al, 1995).…”

Section: Lhmentioning

confidence: 99%

“…Tempol is an amphipathic compound and might be expected to accumulate in the phospholipid outer monolayer of LDL, rather than in its cholesteryl ester core. We suspect the oxidation of LDL by iron at lysosomal pH starts in the core of LDL and then spreads to the phospholipid monolayer (Ahmad and Leake, 2018). Tempol might not be able to scavenge superoxide or hydroperoxyl radicals effectively enough to stop them entering the LDL particles and oxidising its core, but might be able to inhibit the later oxidation of the phospholipid monolayer by scavenging phospholipid peroxyl or alkoxyl radicals.…”

Section: Lhmentioning

confidence: 99%

“…Cysteamine contains a thiol group and effectively inhibits the oxidation of LDL by ferrous iron at lysosomal pH (Ahmad and Leake, 2018). Thiols have previously been seen to act as promoters (Heinecke et al, 1993) or inhibitors of LDL oxidation (Patterson et al, 2003).…”

Section: Lhmentioning

confidence: 99%

“…We now report the ability of ferritin to oxidise LDL effectively at pH 4.5, the pH of lysosomes (Mindell, 2012), and the effect of antioxidants on this oxidation. N,N′-diphenyl-p-phenylenediamine (DPPD), a hydrophobic antioxidant is a potent lipid peroxyl radical scavenger (Tang et al, 2000) and has been shown to inhibit oxidation of LDL (Sparrow et al, 1992, Tangirala et al, 1995, Ahmad and Leake, 2018 and slow down the progression of atherosclerosis (Sparrow et al, 1992, Tangirala et al, 1995. Tempol (4-hydroxy-2,2,6,6tetramethylpiperidine 1-oxyl) has a reducible nitroxide group and is a superoxide dismutase mimetic and can scavenge many reactive oxygen species (Wilcox and Pearlman, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Low density lipoprotein oxidation by ferritin at lysosomal pH

Ojo

Leake

2018

Chemistry and Physics of Lipids

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Oxidation of low density lipoprotein (LDL) has been proposed to be involved in the pathogenesis of atherosclerosis. We have previously shown that LDL can be oxidised by iron in lysosomes. As the iron-storage protein ferritin might enter lysosomes by autophagy, we have investigated the ability of ferritin to catalyse LDL oxidation at lysosomal pH. LDL was incubated with ferritin at 37 o C and pH 4.5 and its oxidation monitored spectrophotometrically at 234 nm by the formation of conjugated dienes and by measuring oxidised lipids by HPLC or a tri-iodide assay. Iron released from ferritin was measured using the ferrous iron chelator bathophenanthroline and by ultrafiltration followed by atomic absorption spectroscopy. LDL was oxidised effectively by ferritin (0.05 -0.2 µM). The oxidation at lysosomal pH (pH 4.5) was much faster than at pH 7.4. Ferritin increased cholesteryl linoleate hydroperoxide, total lipid hydroperoxides and 7-ketocholesterol. Iron was released from ferritin at acidic pH. The iron chelators, diethylenetriaminepentaacetate and EDTA, and antioxidant N,N‫-׳‬diphenyl-p-phenylenediamine inhibited the oxidation considerably, but not entirely. The antioxidant tempol did not inhibit the initial oxidation of LDL, but inhibited its later oxidation.Cysteamine, a lysosomotropic antioxidant, inhibited the initial oxidation of LDL in a concentrationdependent manner, however, the lower concentrations exhibited a pro-oxidant effect at later times, which was diminished and then abolished as the concentration increased. These results suggest that ferritin might play a role in lysosomal LDL oxidation and that antioxidants that accumulate in lysosomes might be a novel therapy for atherosclerosis.

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Section: Lhmentioning

confidence: 99%

Section: Lhmentioning

confidence: 99%

Section: Lhmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low density lipoprotein oxidation by ferritin at lysosomal pH

Ojo

Leake

2018

Chemistry and Physics of Lipids

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“…We have shown previously that LDL can be oxidised by iron in the lysosomes of macrophages [21] and that this causes the secretion of inflammatory cytokines [22]. The antioxidant cysteamine, which accumulates in lysosomes, inhibits the lysosomal oxidation of LDL [22][23][24][25] and decreases atherosclerosis in LDL receptor-deficient mice [25]. The oxidation of LDL by ferrous ion at lysosomal pH (pH 4.5) was not effectively inhibited by a-tocopherol [26].…”

Section: Introductionmentioning

confidence: 98%

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

Alboaklah

Leake

2020

Free Radical Research

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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.

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Natural products: The role and mechanism in low‐density lipoprotein oxidation and atherosclerosis

Zhang

Chen

et al. 2020

Phytotherapy Research

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Atherosclerosis is a chronic inflammatory, metabolic, and epigenetic disease, which leads to the life-threatening coronary artery disease. Emerging studies from bench to bedside have demonstrated the pivotal role of low-density lipoprotein (LDL) oxidation in the initiation and progression of atherosclerosis. This article hereby reviews oxidation mechanism of LDL, and the pro-atherogenic and biomarker role of oxidized LDL in atherosclerosis. We also review the pharmacological effects of several representative natural products (vitamin E, resveratrol, quercetin, probucol, tanshinone IIA, epigallocatechin gallate, and Lycopene) in protecting against LDL oxidation and atherosclerosis. Clinical and basic research supports the beneficial effects of these natural products in inhibiting LDL oxidation and preventing atherosclerosis, but the data are still controversial. This may be related to factors such as the population and the dosage and time of taking natural products involved in different studies. Understanding the mechanism of LDL oxidation and effect of oxidized LDL help researchers to find novel therapies against atherosclerosis.

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Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: A possible explanation as to why the clinical trials of antioxidants might have failed

Cited by 21 publications

References 52 publications

Low density lipoprotein oxidation by ferritin at lysosomal pH

Low density lipoprotein oxidation by ferritin at lysosomal pH

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

Natural products: The role and mechanism in low‐density lipoprotein oxidation and atherosclerosis

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