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Advanced glycation end products upregulate lysyl oxidase and endothelin-1 in human aortic endothelial cells via parallel activation of ERK1/2–NF-κB and JNK–AP-1 signaling pathways

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Abstract

Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-κB and AP-1 potentiation. We hypothesized that AGEs could induce NF-κΒ- and AP-1-dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility-shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE-BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time-dependent fashion. AGE administration significantly increased NF-κΒ- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-κΒ- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation.

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Abbreviations

AGEs:

Advanced glycation end products

AP-1:

Activator protein-1

BAECs:

Bovine aortic endothelial cells

COX-2:

Cyclo-oxygenase-2

CRP:

C-reactive protein

CVD:

Cardiovascular disease

ET-1:

Endothelin-1

HDL:

High-density lipoprotein

ICAM-1:

Intercellular adhesion molecule-1

IL-1β:

Interleukin-1 beta

LDL:

Low-density lipoprotein

LOX:

Lysyl oxidase

MAPK:

Mitogen-activated protein kinase

NF-κB:

Nuclear factor kappa B

NO:

Nitric oxide

PCOS:

Polycystic ovary syndrome

RAGE:

Receptor for AGEs

ROS:

Reactive oxygen species

VEGF:

Vascular endothelial growth factor

VSMCs:

Vascular smooth muscle cells

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Authors and Affiliations

  1. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece

    Christos Adamopoulos, Christina Piperi, Antonios N. Gargalionis, Georgia Dalagiorgou, Eliana Spilioti & Athanasios G. Papavassiliou

  2. First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece

    Penelope Korkolopoulou

  3. Third Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, ‘Sotiria’ Hospital, 11527, Athens, Greece

    Evanthia Diamanti-Kandarakis

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  1. Christos Adamopoulos
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Adamopoulos, C., Piperi, C., Gargalionis, A.N. et al. Advanced glycation end products upregulate lysyl oxidase and endothelin-1 in human aortic endothelial cells via parallel activation of ERK1/2–NF-κB and JNK–AP-1 signaling pathways. Cell. Mol. Life Sci. 73, 1685–1698 (2016). https://doi.org/10.1007/s00018-015-2091-z

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