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Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress

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Abstract

Type 2 Diabetes Mellitus is a worldwide epidemic, and its atherosclerotic complications produce morbidity and mortality in affected patients. It is known that the vascular cell adhesion molecule-1 (VCAM-1) levels are increased in the sera of diabetic patients. Our aim was to investigate the impact of the endoplasmic reticulum stress (ERS) in VCAM-1 expression and secretion in human endothelial cells (HEC) exposed to glycated low-density lipoproteins (gLDL). The results showed that 24 h incubation of HEC with gLDL induces (i) stimulation of VCAM-1 expression and secretion, determining increased monocyte adhesion to HEC; (ii) RAGE up-regulation and free cholesterol loading; (iii) ERS activation (increased eIF2α phosphorylation and CHOP mRNA levels, and decreased GRP78 protein expression); and (iv) oxidative stress [increased levels of reactive oxygen species (ROS) and glutamate cysteine ligase catalytic unit gene expression]. Treatment of gLDL-exposed HEC with ERS inhibitors, salubrinal (Sal) and sodium phenylbutyrate (PBA), decreased intracellular ROS. Incubation of gLDL-exposed cells with the anti-oxidant N-acetyl-cysteine (NAC) reduced ERS, revealed by decreased eIF2α phosphorylation and CHOP gene expression and increased GRP78 expression, thus validating the interconnection between ERS and oxidative stress. Sal, PBA, NAC and inhibitors of p38 MAP kinase and NF-kB induced the decrease of VCAM-1 expression and of the ensuing monocyte adhesion induced by gLDL. In conclusion, in HEC, gLDL stimulate the expression of cellular VCAM-1, the secretion of soluble VCAM-1, and the adhesion of monocytes through mechanisms involving p38 MAP kinase and NF-kB signalling pathways activated by RAGE, ERS and oxidative stress, thus contributing to diabetic atherosclerosis.

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Acknowledgments

The authors thank Ms. Daniela Rogoz and Ms. Cristina Dobre for their skilful technical assistance. This work was supported by the Romanian Academy, the Romanian Ministry of National Education PN-II-PT-PCCA-2011-3.1-0184 project (Grant Number PCCA-127/2012) and PN-II-RU-TE-2014-4-0506 project (Grant Number TE 11/2015).

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Authors and Affiliations

  1. Lipidomics Department, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 8.B.P Hasdeu Street, 050568, Bucharest, Romania

    Laura Toma, Gabriela M. Sanda, Mariana Deleanu, Camelia S. Stancu & Anca V. Sima

  2. Faculty of Biotechnology, University of Agronomical Sciences and Veterinary Medicine, Bucharest, Romania

    Mariana Deleanu

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  1. Laura Toma
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  2. Gabriela M. Sanda
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Correspondence to Anca V. Sima.

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This article is dedicated to the 150th Anniversary of the Romanian Academy.

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Toma, L., Sanda, G.M., Deleanu, M. et al. Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress. Mol Cell Biochem 417, 169–179 (2016). https://doi.org/10.1007/s11010-016-2724-z

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