Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2015 Springer International Publishing.
Συγγραφείς:
Adamopoulos, C.
Piperi, C.
Gargalionis, A.N.
Dalagiorgou, G.
Spilioti, E.
Korkolopoulou, P.
Diamanti-Kandarakis, E.
Papavassiliou, A.G.
Περιοδικό:
Cellular and Molecular Life Sciences (CMLS)
Εκδότης:
Birkhauser Verlag AG
Λέξεις-κλειδιά:
advanced glycation end product; endothelin 1; immunoglobulin enhancer binding protein; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein lysine 6 oxidase; stress activated protein kinase; transcription factor AP 1; transcription factor RelA; advanced glycation end product; advanced glycation end product receptor; endothelin 1; immunoglobulin enhancer binding protein; mitogen activated protein kinase; OLR1 protein, human; oxidized low density lipoprotein receptor 1; protein lysine 6 oxidase; stress activated protein kinase; transcription factor AP 1, animal experiment; animal tissue; aortic endothelial cell; Article; cell proliferation; controlled study; dose time effect relation; endothelial homeostasis; endothelium cell; enzyme activation; enzyme activity; enzyme phosphorylation; ET 1 gene; extracellular matrix; female; fluorescence activated cell sorting; gel mobility shift assay; gene expression regulation; homeostasis; human; human cell; immunohistochemistry; in vitro study; in vivo study; intracellular signaling; LOX gene; molecular dynamics; nonhuman; promoter region; protein expression; rat; real time polymerase chain reaction; reverse transcription polymerase chain reaction; time series analysis; upregulation; animal; aorta; biosynthesis; cell line; cytology; endothelium cell; enzyme activation; metabolism; oxidative stress; physiology; signal transduction; transcription initiation; vascular endothelium; Wistar rat, Advanced Glycosylation End Product-Specific Receptor; Animals; Aorta; Cell Line; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Glycosylation End Products, Advanced; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; NF-kappa B; Oxidative Stress; Protein-Lysine 6-Oxidase; Rats; Rats, Wistar; Scavenger Receptors, Class E; Transcription Factor AP-1; Transcriptional Activation
DOI:
10.1007/s00018-015-2091-z
