Why is cysteamine able to inhibit oxidation of LDL?

The antioxidant effect might possibly be due to the lower availability of iron, as cysteamine might possibly be able to bind to and inactivate iron released from ferritin.

What is the oxidation of low density lipoprotein (LDL)?

The oxidation of low density lipoprotein (LDL) has been proposed to occur in theextracellular space of the arterial wall and lead to the formation of foam cells and atherosclerosis (Steinberg, 2009).

What is the effect of DTPA on the oxidation of LDL?

The iron chelator DTPA completely inhibits the oxidation of LDL catalysed by ferrous ironat acidic pH (Satchell and Leake, 2012).

What is the iron hypothesis of atherosclerosis?

About 30% of the iron in ferritin was released in 24 h.A BThe iron hypothesis of atherosclerosis has been supported indirectly by the availability ofredox-active iron and high levels of both the L and H subunits of the iron storage protein ferritin in atherosclerotic lesions (Smith et al., 1992, Pang et al., 1996, You et al., 2003).

What is the role of DPPD in reducing atherosclerosis?

Its ability to inhibit LDL oxidation by ferritin at lysosomal pH might help to explain why it decreased atherosclerosis in animal models (Sparrow et al., 1992, Tangirala et al., 1995).

What is the role of oxidized LDL in macrophages?

Cholesterol crystals derived from oxidised LDL in lysosomes have been reported to rupture these organelles in macrophages and activate the NLRP3 inflammasome (Duewell et al., 2010).

What is the role of ferritin in oxidizing LDL?

Their hypothesis is that the major iron-storing protein ferritin can oxidise LDL at lysosomal pHand the authors have shown for the first time that it can do so effectively at this pH and that some antioxidants have surprising complex effects on this oxidation.

What was the pH of ferritin incubated alone?

The authors detected very few degradation products in ferritin incubated alone at pH 4.5 when analysed by SDS-polyacrylamide gel electrophoresis (unpublished results).

What is the reason for the rapid oxidation of LDL?

This might imply that in addition to the iron release,reactive oxygen species are formed from inside the ferritin particles which can oxidise LDL.

What is the role of lysosomal antioxidants in atherosclerosis?

The inhibition of lysosomal LDL oxidation by lysosomotropic antioxidants therefore raises a novel therapeutic possibility for atherosclerosis.

What is the effect of the lysosomal antioxidant cysteamine on oxid?

This oxidation was inhibited greatly by high concentrations of the lysosomotropic drug cysteamine, which is already used in patients for the rare lysosomal storage disease cystinosis.

What did the reactive oxygen species scavenger tempol inhibit?

The reactive oxygen species scavenger tempol (10 μM) did not inhibit the initial oxidation ofLDL by ferritin, but inhibited the oxidation later on (Fig. 4B).

Open AccessJournal Article10.1016/J.CHEMPHYSLIP.2018.09.016

Low density lipoprotein oxidation by ferritin at lysosomal pH.

Oluwatosin O. Ojo, +1 more

- 01 Dec 2018

- Chemistry and Physics of Lipids

- Vol. 217, pp 51-57

TL;DR: The results suggest that ferritin might play a role in lysosomal LDL oxidation and that antioxidants that accumulate inLysosomes might be a novel therapy for atherosclerosis.

About: This article is published in Chemistry and Physics of Lipids. The article was published on 01 Dec 2018. and is currently open access. The article focuses on the topics: Ferritin & Low-density lipoprotein.

AI Agents for this Paper

Find similar papers on Google Scholar, PubMed and Arxiv
Write a critical review of this paper
Analyze citations of this paper to find unaddressed research gaps

Most frequently asked questions

1. What contributions have the authors mentioned in the paper "Low density lipoprotein oxidation by ferritin at lysosomal ph" ?

The authors have previously shown that LDL can be oxidised by iron in lysosomes.. As the iron-storage protein ferritin might enter lysosomes by autophagy, the authors have investigated the ability of ferritin to catalyse LDL oxidation at lysosomal pH. LDL was incubated with ferritin at 37 C and pH 4.. Iron released from ferritin was measured using the ferrous iron chelator bathophenanthroline and by ultrafiltration followed by atomic absorption spectroscopy.. 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.

2. What is the reaction of ferritin to the superoxide radical?

The ferrous iron released from ferritin can react with molecular oxygen to produce the superoxide radical (O2.-) (eqn 1) which can protonate at acidic pH to form the hydroperoxyl radical (HO2.)

3. What was the oxidation of LDL in the cuvettes?

An aggregation phase where UV scattering occurred followed by a sedimentation phase (where the LDL aggregates fell below the beam of UV in the cuvettes) was then observed.

4. What is the role of iron in lysosomes?

Redox-active iron in the lysosomes may play a key role in lysosomal LDL oxidation (Wen and Leake, 2007, Satchell and Leake, 2012).

Fig. 1. Effect of ferritin on LDL oxidation. (A) LDL (50 µg protein/ml) was incubated at 37 oC in NaCl/sodium acetate buffer, pH 4.5 in the absence or presence of varying concentrations of ferritin (0.05 µM to 0.2 µM). Formation of conjugated dienes was monitored by measuring attenuance at 234 nm. (B) LDL (50 µg protein/ml) was incubated with different concentrations of ferritin at 37 oC in NaCl/sodium acetate buffer, pH 4.5 or MOPS buffer, pH 7.4. These results are representative of three independent experiments.

Fig. 2. Oxidised lipids in LDL incubated with ferritin at pH 4.5. LDL (50 µg protein/ml) was incubated with or without ferritin (0.1 µM) in sodium acetate buffer (pH 4.5) at 37 oC. The samples were assayed for cholesteryl linoleate hydroperoxide (CLOOH) (A) and 7-ketocholesterol (B) by reverse-phase HPLC and for total hydroperoxide content by a tri-iodide assay (C). The mean ± SEM of three independent experiments are shown. Difference between control LDL and LDL oxidised by ferritin at each time point were determined by two-way ANOVA with Bonferroni post-tests. * indicates p<0.05, ** indicates p<0.01,*** indicates p<0.001

Fig. 5. The effect of cysteamine on LDL oxidation by ferritin. LDL (50 µg protein/ml) was oxidised with ferritin (0.1 µM) in sodium acetate buffer (pH 4.5) at 37 oC with 5 – 1000 µM (A) or 1 – 10 mM (B) cysteamine. The formation of conjugated dienes was monitored by measuring attenuance at 234 nm. For the colour version of (A), the colours of the lines correspond to the concentrations of cysteamine as follows: red 0, yellow 5, grey 10, purple 25, green 100, blue 250 and black 1,000 μM. For (B), the colours of the lines correspond to the concentrations of cysteamine as follows: red 0, black 1, brown 3 and green 10 mM. Ferritin (0.1 µM) was incubated at 37 ˚C in NaCl/Na acetate buffer (pH 4.5) in the absence or presence of cysteamine (25 µM) (C) or 1 mM (D). At different times, a sample (1 ml) was taken and the ferrous chelator bathophenanthroline was added, left for 5 min and the absorbance was measured at 535 nm (* indicates p<0.05, *** indicates p<0.001). These results are representative of three independent experiments

Fig. 3. Determination of iron released from ferritin and effect of iron chelators. (A) Ferritin (0.1 µM) was incubated at 37 ˚C in NaCl/Na acetate buffer (pH 4.5) or MOPS buffer (pH 7.4). At different times, a sample (1 ml) was taken and the ferrous chelator bathophenanthroline was added left for 5 min and the absorbance was measured at 535 nm. The means of three independent experiments are shown. (B) LDL (50 µg protein/ml) was oxidised by ferritin (0.1 µM) in sodium acetate buffer (pH 4.5) at 37 oC in the absence or presence of the iron chelators, EDTA (100 µM) and DTPA (100 µM). The formation of conjugated dienes was monitored by measuring attenuance at 234 nm. These results are representative of three independent experiments.

Fig. 4. The effect of DPPD and tempol on LDL oxidation by ferritin. LDL was incubated with ferritin (0.1 µM) at pH 4.5 in the presence of (A) DPPD (5 or10 µM) or ethanol (1% v/v) as a control or (B) tempol (10 μM) in duplicate or without additions in quadruplicate. These results are representative of three independent experiments for DPPD and were replicated six times for tempol. Tempol did not inhibit the early oxidation in all six experiments, but inhibited the later oxidation substantially but partially, as shown here, in three experiments or totally in three experiments.

Citations

•Journal Article•10.3389/FCELL.2021.658995

Lysosome (Dys)function in Atherosclerosis-A Big Weight on the Shoulders of a Small Organelle.

André R. A. Marques, +3 more

- 29 Mar 2021

- Frontiers in Cell and Developmental Biol...

TL;DR: In this paper, the authors summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells and further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the Lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.

...read moreread less

•Journal Article•10.1016/J.JBC.2021.100948

Recognition of lipoproteins by scavenger receptor class A members.

Chen Cheng, +7 more

- 01 Aug 2021

- Journal of Biological Chemistry

TL;DR: In this paper, the authors systematically characterize the recognition of scavenger receptors with lipoproteins and report that SCARA1 (SR-A1, CD204), MARCO (SCARA2), and SCARA5 recognize acetylated or oxidized LDL and very-low-density lipoprotein in a Ca2+-dependent manner through their C-terminal scavenger receptor cysteine-rich (SRCR) domains.

...read moreread less

•Journal Article•10.1016/J.ATHEROSCLEROSIS.2019.09.019

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

Yichuan Wen, +4 more

- 01 Jun 2018

- Atherosclerosis

TL;DR: The hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysOSomes might provide a novel therapy for this disease is supported.

...read moreread less

•Journal Article•10.3390/polym14214778

Ligustrazine as an Extract from Medicinal and Edible Plant Chuanxiong Encapsulated in Liposome–Hydrogel Exerting Antioxidant Effect on Preventing Skin Photoaging

Hongmei Xia, +1 more

- 07 Nov 2022

- Polymers

TL;DR: In this paper , a ligustrazine hydrochloride (TMPZ)-loaded liposome-hydrogel was applied on the skin of mice to observe whether it had preventive and therapeutic effect on the irradiation under the ultraviolet rays.

...read moreread less

•Journal Article•10.1080/10715762.2021.1964494

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

Oluwatosin O. Ojo, +1 more

- 16 Aug 2021

- Free Radical Research

TL;DR: In this paper, the roles of the most important antioxidant contained in LDL, α-tocopherol (the main form of vitamin E) and of ascorbate (vitamin C), a major water-soluble antioxidant, on LDL oxidation by ferritin at lysosomal pH (pH 4.5).

...read moreread less

References

•Journal Article•10.1161/01.CIR.86.3.803

High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men.

Jukka T. Salonen, +5 more

- 01 Sep 1992

- Circulation

TL;DR: The data suggest that a high stored iron level, as assessed by elevated serum ferritin concentration, is a risk factor for coronary heart disease.

...read moreread less

1.2K

•Journal Article•10.1146/ANNUREV-PHYSIOL-012110-142317

Lysosomal Acidification Mechanisms

Joseph A. Mindell

- 15 Feb 2012

- Annual Review of Physiology

TL;DR: Both the V-ATPase and the counterion transporter are likely to be important players in the mechanisms determining the steady-state pH of the lysosome interior.

...read moreread less

Journal Article•10.1016/S0140-6736(81)92463-6

Iron and the sex difference in heart disease risk

Jerome L. Sullivan

- 13 Jun 1981

- The Lancet

TL;DR: The hypothesis offered is that the greater incidence of heart diseases in men and postmenopausal women compared with the incidence in premenopausalWomen is due to higher levels of stored iron in these two groups, and the heart diseases of affluence are rare among impoverished peoples who are often iron deficient.

...read moreread less

984

Journal Article•10.1126/SCIENCE.2452485

Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation

John L. Casey, +6 more

- 13 May 1988

- Science

TL;DR: The 3' untranslated region of the mRNA for the human TfR was shown to be necessary and sufficient for iron-dependent control of mRNA levels and an mRNA element has been implicated in the mediation of distinct regulatory phenomena dependent on the context of the element within the transcript.

...read moreread less

742

•Journal Article•10.1016/S0022-2275(20)38354-1

A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent.

M. A. El-Saadani, +5 more

- 01 Apr 1989

- Journal of Lipid Research

TL;DR: The ability to estimate lipid peroxides of isolated low density lipoprotein was demonstrated and a stoichiometric relationship was observed between the amount of organic peroxide assayed and the concentration of iodine produced.

...read moreread less

649

...

Expand

Low density lipoprotein oxidation by ferritin at lysosomal pH.

Chat with Paper

AI Agents for this Paper

Most frequently asked questions

1. What contributions have the authors mentioned in the paper "Low density lipoprotein oxidation by ferritin at lysosomal ph" ?

2. What is the reaction of ferritin to the superoxide radical?

3. What was the oxidation of LDL in the cuvettes?

4. What is the role of iron in lysosomes?

5. Why is cysteamine able to inhibit oxidation of LDL?

6. What is the oxidation of low density lipoprotein (LDL)?

7. What is the effect of DTPA on the oxidation of LDL?

8. What is the iron hypothesis of atherosclerosis?

9. What is the role of DPPD in reducing atherosclerosis?

10. What is the role of oxidized LDL in macrophages?

11. What is the role of ferritin in oxidizing LDL?

12. What was the pH of ferritin incubated alone?

13. What is the reason for the rapid oxidation of LDL?

14. What is the role of lysosomal antioxidants in atherosclerosis?

15. What is the effect of the lysosomal antioxidant cysteamine on oxid?

16. What did the reactive oxygen species scavenger tempol inhibit?

Figures

Citations

Lysosome (Dys)function in Atherosclerosis-A Big Weight on the Shoulders of a Small Organelle.

Recognition of lipoproteins by scavenger receptor class A members.

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

Ligustrazine as an Extract from Medicinal and Edible Plant Chuanxiong Encapsulated in Liposome–Hydrogel Exerting Antioxidant Effect on Preventing Skin Photoaging

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

References

High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men.

Lysosomal Acidification Mechanisms

Iron and the sex difference in heart disease risk

Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation

A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent.

Related Papers (5)

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

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

Macrophage-mediated oxidation of extracellular low density lipoprotein requires an initial binding of the lipoprotein to its receptor.

Macrophages Require Both Iron and Copper to Oxidize Low-Density Lipoprotein in Hanks’ Balanced Salt Solution

Oxidation of LDL to a biologically active form by derivatives of nitric oxide and nitrite in the absence of superoxide. Dependence on pH and oxygen.