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

被引:82
作者
Adamopoulos, Christos [1 ]
Piperi, Christina [1 ]
Gargalionis, Antonios N. [1 ]
Dalagiorgou, Georgia [1 ]
Spilioti, Eliana [1 ]
Korkolopoulou, Penelope [2 ]
Diamanti-Kandarakis, Evanthia [3 ]
Papavassiliou, Athanasios G. [1 ]
机构
[1] Univ Athens, Sch Med, Dept Biol Chem, 75 M Asias St, Athens 11527, Greece
[2] Univ Athens, Sch Med, Dept Pathol 1, Athens 11527, Greece
[3] Univ Athens, Sch Med, Dept Internal Med 3, Sotiria Hosp, Athens 11527, Greece
关键词
AGEs; RAGE; Lysyl oxidase; Endothelin-1; Endothelial dysfunction; Signaling pathways; FACTOR-KAPPA-B; CORONARY-ARTERY; NITRIC-OXIDE; IN-VITRO; CLINICAL-IMPLICATIONS; DIABETES-MELLITUS; KINASE PATHWAY; TNF-ALPHA; DYSFUNCTION; RAGE;
D O I
10.1007/s00018-015-2091-z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappa B) 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-kappa B and AP-1 potentiation. We hypothesized that AGEs could induce NF-kappa I'- 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-kappa I'- 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-kappa I'- 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.
引用
收藏
页码:1685 / 1698
页数:14
相关论文
共 67 条
[1]   CLOSE RELATION OF ENDOTHELIAL FUNCTION IN THE HUMAN CORONARY AND PERIPHERAL CIRCULATIONS [J].
ANDERSON, TJ ;
UEHATA, A ;
GERHARD, MD ;
MEREDITH, IT ;
KNAB, S ;
DELAGRANGE, D ;
LIEBERMAN, EH ;
GANZ, P ;
CREAGER, MA ;
YEUNG, AC ;
SELWYN, AP .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1995, 26 (05) :1235-1241
[2]   Endothelin peptide and receptors in human atherosclerotic coronary artery and aorta [J].
Bacon, CR ;
Cary, NR ;
Davenport, AP .
CIRCULATION RESEARCH, 1996, 79 (04) :794-801
[3]   Advanced glycation end products activate endothelium through signal-transduction receptor RAGE - A mechanism for amplification of inflammatory responses [J].
Basta, G ;
Lazzerini, G ;
Massaro, M ;
Simoncini, T ;
Tanganelli, P ;
Fu, CF ;
Kislinger, T ;
Stern, DM ;
Schmidt, AM ;
De Caterina, R .
CIRCULATION, 2002, 105 (07) :816-822
[4]   S100B binding to RAGE in microglia stimulates COX-2 expression [J].
Bianchi, Roberta ;
Adami, Cecilia ;
Giambanco, Ileana ;
Donato, Rosario .
JOURNAL OF LEUKOCYTE BIOLOGY, 2007, 81 (01) :108-118
[5]   S100B/RAGE-dependent activation of microglia via NF-κB and AP-1 Co-regulation of COX-2 expression by S100B, IL-1β and TNF-α [J].
Bianchi, Roberta ;
Giambanco, Ileana ;
Donato, Rosario .
NEUROBIOLOGY OF AGING, 2010, 31 (04) :665-677
[6]   Advanced glycation end product-induced activation of NF-kappa B is suppressed by alpha-lipoic acid in cultured endothelial cells [J].
Bierhaus, A ;
Chevion, S ;
Chevion, M ;
Hofmann, M ;
Quehenberger, P ;
Illmer, T ;
Luther, T ;
Berentshtein, E ;
Tritschler, H ;
Muller, M ;
Wahl, P ;
Ziegler, R ;
Nawroth, PP .
DIABETES, 1997, 46 (09) :1481-1490
[7]   Endothelial dysfunction - A marker of atherosclerotic risk [J].
Bonetti, PO ;
Lerman, LO ;
Lerman, A .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2003, 23 (02) :168-175
[8]   The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives [J].
Bourque, Stephane L. ;
Davidge, Sandra T. ;
Adams, Michael A. .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2011, 300 (06) :R1288-R1295
[9]   ADVANCED PROTEIN GLYCOSYLATION IN DIABETES AND AGING [J].
BROWNLEE, M .
ANNUAL REVIEW OF MEDICINE, 1995, 46 :223-234
[10]   Changes in biomechanical properties, composition of collagen and elastin, and advanced glycation endproducts of the rat aorta in relation to age [J].
Bruel, A ;
Oxlund, H .
ATHEROSCLEROSIS, 1996, 127 (02) :155-165