S-homocysteinylated LDL apolipoprotein B adversely affects human endothelial cells in vitro

Zinellu, Angelo; Sotgia, Salvatore; Scanu, Bastianina; Pintus, Gianfranco; Posadino, Anna Maria; Cossu, Annalisa; Deiana, Luca; Sengupta, Shantanu; Carru, Ciriaco

doi:10.1016/j.atherosclerosis.2009.01.035

Cited by 34 publications

(26 citation statements)

References 36 publications

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“…By multiple regression analysis it also emerged that, as for the normal population, Cys-Gly seemed to inhibit the interaction between Hcy and LDL also in CKD, thus confirming our previous hypothesis on the possible protective role of this molecule toward the proatherogenic modification of LDL [22,23]. We found that the relative quantity of Cys-Gly is higher in the apoprotein fraction than in plasma both in controls and CKD patients, thus confirming our previous data on the high affinity of apoB for Cys-Gly.…”

Section: Discussionsupporting

confidence: 68%

“…Given that at least 5 low molecular mass aminothiols occur in plasma, Hcy competes with other thiols for binding to the accessible –SH sites. Our previous results showed that increasing concentrations of plasma Hcy lead to higher S-homocysteinylation of lipoproteins in vivo [23,30]. These data have been confirmed by in vitro experiments which clearly show that Hcy binds to apoprotein through a disulfide bond in a dependent manner concentration.…”

Section: Discussionsupporting

confidence: 66%

“…The amount of thiols displaced from apoprotein is also dependent on the amount of Hcy added. We also found that Cys-Gly seems to resist to the displacement better than other thiols [23,24,25,26,27,28,29,30]. …”

Section: Discussionmentioning

confidence: 88%

“…Our results showed that increasing concentrations of plasma Hcy lead to higher S-homocysteinylation of lipoprotein in vivo. Moreover, our in vitro studies on the effect of Hcy-S-LDL on cultured human endothelial cells have shown an increase of intracellular reactive oxygen species (ROS) production and a reduced proliferation and viability of cells after incubation with homocysteinylated LDL, suggesting an antiangiogenic and proatherogenic role of this type of LDL modification [23]. In proteinuric patients, dyslipidemia has a highly atherogenic profile, with increased total and LDL cholesterol, triglyceride, and a decreased high-density lipoprotein (HDL) cholesterol [24,25].…”

Section: Introductionmentioning

confidence: 99%

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Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

Zinellu

Loriga²,

Scanu³

et al. 2010

Am J Nephrol

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Background: Since low-density lipoprotein (LDL) S-homocysteinylation has been recently reported to enhance atherogenicity of lipoprotein, we have investigated the levels of homocysteine (Hcy) linked to LDL in chronic proteinuric patients in which lipid abnormalities highly contribute to the excess of morbidity and mortality. Methods: We used capillary electrophoresis to measure LDL-bound thiol Hcy, cysteine (Cys), cysteinylglycine (Cys-Gly), glutathione (GSH), and glutamylcysteine (Glu-Cys) in 30 chronic kidney disease (CKD) individuals and 60 healthy volunteers. Results: We found more elevated levels of total plasma Hcy, Cys, GSH and Glu-Cys in patients than in controls and also found that Hcy and Cys bound to LDL were significantly increased in nephropathic subjects. By multiple linear regression, we found that in healthy people, total Hcy was the most important determinant of LDL-bound Hcy and Cys-Gly was negatively associated with apoB-Hcy concentrations. In CKD the most important determinant of homocysteinylation was creatinine while total plasma Hcy is weakly associated with apoB-Hcy. Conclusions: The increased levels in Hcy-LDL observed in CKD patients might account, at least in part, for the excess of cardiovascular risk; thus LDL S-homocysteinylation can be considered a key marker of risk for cardiovascular disease in these individuals.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

Zinellu

Loriga²,

Scanu³

et al. 2010

Am J Nephrol

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“…Several hypotheses have been put forward to explain the deleterious effects of homocysteine. Prominent among these are the stress hypothesis (oxidative and endoplasmic reticulum stress) (8 -10), molecular targeting hypothesis (ability of homocysteine to bind to free cysteine residues or break critical cysteine disulfide bonds thereby altering the structure and function of the protein) (11)(12)(13)(14), and ability of homocysteine to alter the methylation status of DNA, RNA, proteins, and other metabolites (15). We believe that although these hypotheses have been proven beyond doubt under the conditions for which it has been tested, any one of these mechanisms cannot account for the toxicity of this thiol compound under all conditions.…”

mentioning

confidence: 99%

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Kumar¹,

John

Maity

et al. 2011

Journal of Biological Chemistry

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An elevated level of homocysteine, a thiol amino acid, is associated with various complex disorders. The cellular effects of homocysteine and its precursors S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) are, however, poorly understood. We used Saccharomyces cerevisiae as a model to understand the basis of pathogenicity induced by homocysteine and its precursors. Both homocysteine and AdoHcy but not AdoMet inhibited the growth of the str4⌬ strain (which lacks the enzyme that converts homocysteine to cystathioninemimicking vascular cells). Addition of AdoMet abrogated the inhibitory effect of AdoHcy but not that of homocysteine indicating that an increase in the AdoMet/AdoHcy ratio is sufficient to overcome the AdoHcy-mediated growth defect but not that of homocysteine. Also, the transcriptomic profile of AdoHcy and homocysteine showed gross dissimilarity based on gene enrichment analysis. Furthermore, compared with homocysteine, AdoHcy treatment caused a higher level of oxidative stress in the cells. However, unlike a previously reported response in wild type (Kumar, A., John, L., Alam, M. M., Gupta, A., Sharma, G., Pillai, B., and Sengupta, S. (2006) Biochem. J. 396, 61-69), the str4⌬ strain did not exhibit an endoplasmic reticulum stress response. This suggests that homocysteine induces varied response depending on the flux of homocysteine metabolism. We also observed altered expression of mitochondrial genes, defective membrane potential, and fragmentation of the mitochondrial network together with the increased expression of fission genes indicating that the imbalance in homocysteine metabolism has a major effect on mitochondrial functions. Furthermore, treatment of cells with homocysteine or AdoHcy resulted in apoptosis as revealed by annexin V staining and TUNEL assay. Cumulatively, our results suggest that elevated levels of homocysteine lead to mitochondrial dysfunction, which could potentially initiate pro-apoptotic pathways, and this could be one of the mechanisms underlying homocysteineinduced pathogenicity.

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Oxidized Low-Density Lipoprotein: Preparation, Validation, and Use in Cell Models

Angayarkanni,

Anand Babu

2024

Methods in Molecular Biology

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S-homocysteinylated LDL apolipoprotein B adversely affects human endothelial cells in vitro

Cited by 34 publications

References 36 publications

Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Oxidized Low-Density Lipoprotein: Preparation, Validation, and Use in Cell Models

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