High glucose conditions induce upregulation of fractalkine and monocyte chemotactic protein-1 in human smooth muscle cells.
The major complication of diabetes mellitus is accelerated atherosclerosis that entails an inflammatory process, in which fractalkine and monocyte chemotactic protein-1 (MCP-1) play a key role. We investigated the effect of diabetes-associated high glucose (HG) on these chemokines and signalling mechanisms involved in human aortic smooth muscle cells (SMC). Exposure of SMC to HG resulted in an increase of fractalkine and MCP-1 expression and the activated mitogen-activated protein kinase (MAPK) signalling pathway, a process associated with elevated oxidative stress. Transfection with decoy oligodeoxynucleotides identified the involvement of transcription factors activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappaB) in the observed up-regulation of chemokines. The MAPK inhibitors blocked the phosphorylation of IkBalpha and c-jun, indicating the role of MAPK in NF-kappaB and AP-1 activation in SMC under HG conditions. The up-regulation of MCP-1 and fractalkine was associated with increased adhesive interactions between HG-exposed SMC and monocytes. Treatment of HG-exposed SMC with peroxisome proliferator-activated receptors alpha (PPARalpha) activators (fenofibrate and clofibrate) resulted in a reduction of mRNA and protein expression of MCP-1 and fractalkine. In conclusion, HG upregulates the expression of fractalkine and MCP-1 in SMC leading to increased monocyte-SMC adhesive interactions by a mechanism involving activation of MAPK, activator protein-1 (AP-1) and NF-kappaB. The increased expression of these two pro-inflammatory chemokines and the ensuing increased adhesion between SMC and monocytes may trigger the inflammatory process associated with further vascular complications of diabetes.
Dragomir
Elena
E
Institute of Cellular Biology and Pathology Nicolae Simionescu, BP Hasdeu Street, PO Box 35-14, 79691-Bucharest, Romania.
Manduteanu
Ileana
I
Calin
Manuela
M
Gan
Ana Maria
AM
Stan
Daniela
D
Koenen
Rory Ryan
RR
Weber
Christian
C
Simionescu
Maya
M
D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C111835:CCL2 protein, human; C515538:CX3CL1 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D005419:Flavonoids; D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D047493:PPAR alpha; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D002994:Clofibrate; D005947:Glucose; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D011345:Fenofibrate