Oxidative Modifications of APOB-100 by Exposure of Low Density Lipoproteins to HOCl In Vitro

Yang, Chao; Gu, Zi Wei; Yang, Hui; Yang, Manlan; Gotto, Antonio M.; Smith, Charles V.

doi:10.1016/s0891-5849(96)00624-7

Cited by 76 publications

(67 citation statements)

References 33 publications

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“…This result confirms that the dissociation of α 2 M into dimers and the associated increase in chaperone activity are not exclusively dependent on oxidation but can be accomplished by other types of chemical modification. (4,6,38). As has been shown for many other proteins, incubation of FGN or LDL with hypochlorite induces their self-aggregation into high-molecular mass complexes (1,39,40).…”

Section: Resultsmentioning

confidence: 75%

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer's disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human α 2 -macroglobulin (α 2 M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric α 2 M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified α 2 M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid β-peptide (Aβ 1-42 ). Here, we show that hypochlorite-modified α 2 M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Aβ 1-42 neurotoxicity. Our results support the conclusion that α 2 M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity. molecular chaperone | inflammation | protein folding | clearance H ypochlorite, a potent oxidant produced by immune cells through the myeloperoxidase-H 2 O 2 -chloride system, kills invading microbes predominately by inducing the misfolding and aggregation of their proteins (1). The effects of hypochlorite, however, are nonspecific; therefore, when generated in vivo, the host organism suffers collateral damage (reviewed in refs. 2 and 3). During inflammation, hypochlorite production is accompanied by additional stresses, which are themselves capable of inducing protein misfolding (e.g., increased temperature and lowered pH); it is, therefore, not surprising that, in a large number of diseases [e.g., atherosclerosis (4), Alzheimer's disease (5, 6), age-related macular degeneration (7), and arthritis (8)], inflammatory pathology is associated with the accumulation of misfolded proteins.α 2 -Macroglobulin (α 2 M) is a highly abundant secreted protein that is best known for its ability to trap proteases (9); α 2 M can, however, interact with a broad range of molecules, and consequently, many other biological roles have been suggested, including targeting cytokines for clearance, sequestration of zinc, and opsonization of bacteria (reviewed in ref. 10). Furthermore, α 2 M has been identified as one of a small number of abundant extracellular chaperones (11). Although our un...

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Section: Resultsmentioning

confidence: 75%

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, in some cases, the steric hindrance of N-terminal region of peptides has been known to cause threefold to fourfold lower radiochemical yields [7]- [9]. The unsuitability of amine reactive prosthetic groups for certain peptides has generated interest in developing thiol reactive prosthetic groups that promise to be more selective.…”

Section: F-labeled Bifunctional Agents N-succinimidyl-4-[mentioning

confidence: 99%

Fluorine-18 Radiochemistry: A Novel Thiol-Reactive Prosthetic Group, [18F]FBAMPy

Moore¹,

Akula²,

Kabalka³

2016

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“…Characteristis of the model employed Main observation (Batthyány et al 2000) Copper binding to apolipoprotein B-100 is necessary for oxidation Formation of protein-tryptophanyl radicals (Yang et al 1997) LDL treated with HOCL Selective process of modification of apoB-100 by HOCL (Hedrick et al 2000) Incubation of HDL under hyperglycaemic conditions Changes in HDL caused by hyperglycaemia contribute to accelerated atherosclerosis (Chantepie et al 2009) HDL treated with HOCL Small, dense HDL less susceptible to oxidative modification (Sigalov & Stern 2001) Reconstituted HDL containing oxidized apo A-I Destabilization of the oxidized protein to denaturation (Chen et al 2007) VLDL oxidation induced by peroxyl radicals and peroxynitrite…”

Section: Protein Oxidation "In Vitro"mentioning

confidence: 99%

“…; cupric ion (Batthyány et al 2000), HOCl (Yang et al 1997) or glycation mimicking diabetic conditions (Hedrick et al 2000). More complex systems using "in vitro" cells systems had also been used.…”

Section: "In Vitro" Protein Oxidationmentioning

confidence: 99%

Relationship Between Protein Oxidation Markers and Oxidative Stress Biomarkers

Kivatinitz¹

2012

Inflammatory Diseases - Immunopathology, Clinical and Pharmacological Bases

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Oxidative Modifications of APOB-100 by Exposure of Low Density Lipoproteins to HOCl In Vitro

Cited by 76 publications

References 33 publications

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Fluorine-18 Radiochemistry: A Novel Thiol-Reactive Prosthetic Group, [18F]FBAMPy

Relationship Between Protein Oxidation Markers and Oxidative Stress Biomarkers

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Oxidative Modifications of APOB-100 by Exposure of Low Density Lipoproteins to HOCl In Vitro

Cited by 76 publications

References 33 publications

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Fluorine-18 Radiochemistry: A Novel Thiol-Reactive Prosthetic Group, [18F]FBAMPy

Relationship Between Protein Oxidation Markers and Oxidative Stress Biomarkers

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Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin