Antithrombin activity is inhibited by acrolein and homocysteine thiolactone: Protection by cysteine

Gugliucci, Alejandro

doi:10.1016/j.lfs.2007.11.023

Cited by 17 publications

(13 citation statements)

References 32 publications

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“…Upon platelet activation PF4, released from the α-granules of platelets, binds to heparin-like molecules and prevents the activation of antithrombin (Denton et al , 1983); thereby facilitating thrombus formation at the site of vessel injury. Our data complement recent studies showing that acrolein in vitro inhibits plasma antithrombin activity by inhibiting heparin affinity (Gugliucci, 2008; Martinez-Martinez et al , 2009). Lower antithrombin activity levels could potentially increase thrombin availability in the circulation, adding another pro-thrombotic component to the effects of acrolein exposure.…”

Section: Discussionsupporting

confidence: 90%

Exposure to acrolein by inhalation causes platelet activation

Sithu

Srivastava

Siddiqui

et al. 2010

Toxicology and Applied Pharmacology

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Acrolein is a common air pollutant that is present in high concentrations in wood, cotton, and tobacco smoke, automobile exhaust and industrial waste and emissions. Exposure to acrolein containing environmental pollutants such as tobacco smoke and automobile exhaust has been linked to the activation of the coagulation and hemostasis pathways and thereby to the predisposition of thrombotic events in human. To examine the effects of acrolein on platelets, adult male C57Bl/6 mice were subjected acute (5 ppm for 6 h) or sub-chronic (1 ppm, 6h/day for 4 days) acrolein inhalation exposures. The acute exposure to acrolein did not cause pulmonary inflammation and oxidative stress, dyslipidemia or induce liver damage or muscle injury. Platelet GSH levels in acrolein-exposed mice were comparable to controls, but acrolein-exposure increased the abundance of protein-acrolein adducts in platelets. Platelets isolated from mice, exposed to both acute and sub-chronic acrolein levels, showed increased ADP-induced platelet aggregation. Exposure to acrolein also led to an increase in the indices of platelet activation such as the formation of platelet-leukocyte aggregates in the blood, plasma PF4 levels, and increased platelet-fibrinogen binding. The bleeding time was decreased in acrolein exposed mice. Plasma levels of PF4 were also increased in mice exposed to environmental tobacco smoke. Similar to inhalation exposure, acrolein feeding to mice also increased platelet activation and established a pro-thrombotic state in mice. Together, our data suggest that acrolein is an important contributing factor to the pro-thrombotic risk in human exposure to pollutants such as tobacco smoke or automobile exhaust, or through dietary consumption.

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Section: Discussionsupporting

confidence: 90%

Exposure to acrolein by inhalation causes platelet activation

Sithu

Srivastava

Siddiqui

et al. 2010

Toxicology and Applied Pharmacology

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“…The loss of activity was believed to be due to the modifications of some exposed Lys residues, particularly Lys11, Lys114, and Lys125, occurring on the serpin and affecting the heparin-binding domain, but no unequivocal characterization of the modification sites on the protein has been carried out. The same mechanism of antithrombin inhibition by ACR and the same hypothesis on the modification sites were previously postulated by Gugliucci [55]. In addition, because high concentrations of ACR are required to cause mild functional effects in vivo, although increased levels of ACR may contribute to the risk of thrombosis, it can be concluded that the clinical relevance in thrombosis is to be considered as minor.…”

Section: In Vitro Evidencesupporting

confidence: 68%

Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

Aldini

Orioli

Carini

2011

Molecular Nutrition Food Res

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Acrolein (ACR) is a toxic and highly reactive α,β-unsaturated aldehyde widely distributed in the environment as a common pollutant and generated endogenously mainly by lipoxidation reactions. Its biological effects are due to its ability to react with the nucleophilic sites of proteins, to form covalently modified biomolecules which are thought to be involved as pathogenic factors in the onset and progression of many pathological conditions such as cardiovascular and neurodegenerative diseases. Functional impairment of structural proteins and enzymes by covalent modification (crosslinking) and triggering of key cell signalling systems are now well-recognized signs of cell and tissue damage induced by reactive carbonyl species (RCS). In this review, we mainly focus on the in vitro and in vivo evidence demonstrating the ability of ACR to covalently modify protein structures, in order to gain a deeper insight into the dysregulation of cellular and metabolic pathways caused by such modifications. In addition, by considering RCS and RCS-modified proteins as drug targets, this survey will provide an overview on the newly developed molecules specifically tested for direct or indirect ACR scavenging, and the more significant studies performed in the last years attesting the efficacy of compounds already recognized as promising aldehyde-sequestering agents.

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“…The exogenous administration of NAC or cysteine has received attention to attenuate ACR-related toxicity [38]. As indicated in protein models, the inhibited activities of human PON-1 (aryldialkylphosphatase, EC 3.1.8.1) [53] and human antithrombin (AT) by ACR were attenuated with the addition of cysteine [54]. In the cell models, the protective effect of NAC against ACR was observed, as evidenced by the increased cell survival [55][56][57], as well as in the regulation of multiple factors related to cell viability.…”

Section: Impact On Healthmentioning

confidence: 99%

“…However, little information is available about its trapping efficacy against ACR. Only recently, aminoguanidine was reported to exhibit weaker effects than cysteine to block the loss of activity caused by ACR in human PON-1 and human AT [53,54]. Another issue making aminoguanidine less attractive as an ACR scavenging is its serious adverse effect in clinical trials.…”

Section: Impact On Healthmentioning

confidence: 99%

Acrolein scavengers: Reactivity, mechanism and impact on health

Zhu

Sun

Jiang

et al. 2011

Molecular Nutrition Food Res

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Acrolein (ACR) is an α,β-unsaturated aldehyde that exists extensively in the environment and (thermally processed) foods. It can also be generated through endogenous metabolism. Its high electrophilicity makes this aldehyde notorious for its facile reaction with biological nucleophiles, leading to the modification of proteins/DNA and depletion of glutathione. Recent studies also have revealed its roles in disturbing various cell signing pathways in biological systems. With growing evidences of ACR's implication in human diseases, strategies to eliminate its hazardous impacts are of great importance. One of the intervention strategies is the application of reactive scavengers to directly trap ACR. Some known ACR scavengers include sulfur (thiol)-containing and nitrogen (amino)-containing compounds as well as the newly emerging natural polyphenols. In this review, the interactions between ACR and its scavengers are highlighted. The discussion about ACR scavengers is mainly focused on their chemical reactivity, trapping mechanisms as well as their roles extended to biological relevance. In addition to their direct trapping effect on ACR, these scavengers might possess multiple functions and offer additional benefits against ACR-induced toxicity. A comprehensive understanding of the mechanism involved may help to establish ACR scavenging as a novel therapeutic intervention against human diseases that are associated with ACR and/or oxidative stress.

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Antithrombin activity is inhibited by acrolein and homocysteine thiolactone: Protection by cysteine

Cited by 17 publications

References 32 publications

Exposure to acrolein by inhalation causes platelet activation

Exposure to acrolein by inhalation causes platelet activation

Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

Acrolein scavengers: Reactivity, mechanism and impact on health

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