title: Inflammation determines the pro-adhesive properties of high extracellular d-glucose in human endothelial cells in vitro and rat microvessels in vivo.
abstract: BACKGROUND
  Hyperglycemia is acknowledged as an independent risk factor for developing diabetes-associated atherosclerosis. At present, most therapeutic approaches are targeted at a tight glycemic control in diabetic patients, although this fails to prevent macrovascular complications of the disease. Indeed, it remains highly controversial whether or not the mere elevation of extracellular D-glucose can directly promote vascular inflammation, which favors early pro-atherosclerotic events.
  
  
  RESULTS
  In the present work, increasing extracellular D-glucose from 5.5 to 22 mmol/L was neither sufficient to induce intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, analyzed by flow cytometry, nor to promote leukocyte adhesion to human umbilical vein endothelial cells (HUVEC) in vitro, measured by flow chamber assays. Interestingly, the elevation of D-glucose levels potentiated ICAM-1 and VCAM-1 expression and leukocyte adhesion induced by a pro-inflammatory stimulus, such as interleukin (IL)-1beta (5 ng/mL). In HUVEC, high D-glucose augmented the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and nuclear transcription factor-kappaB (NF-kappaB) elicited by IL-1beta, measured by Western blot and electromobility shift assay (EMSA), respectively, but had no effect by itself. Both ERK 1/2 and NF-kappaB were necessary for VCAM-1 expression, but not for ICAM-1 expression. In vivo, leukocyte trafficking was evaluated in the rat mesenteric microcirculation by intravital microscopy. In accordance with the in vitro data, the acute intraperitoneal injection of D-glucose increased leukocyte rolling flux, adhesion and migration, but only when IL-1beta was co-administered.
  
  
  CONCLUSIONS
  These results indicate that the elevation of extracellular D-glucose levels is not sufficient to promote vascular inflammation, and they highlight the pivotal role of a pro-inflammatory environment in diabetes, as a critical factor conditioning the early pro-atherosclerotic actions of hyperglycemia.
authors.affiliation: Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Azcutia
authors.forename: May
authors.initials: M
authors.lastname: Abu-Taha
authors.forename: Tania
authors.initials: T
authors.lastname: Romacho
authors.forename: Marta
authors.initials: M
authors.lastname: Vázquez-Bella
authors.forename: Nuria
authors.initials: N
authors.lastname: Matesanz
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
authors.forename: Leocadio
authors.initials: L
authors.lastname: Rodríguez-Mañas
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
mesh_terms: D000268:Adhesiveness; D000818:Animals; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D036904:Leukocyte Rolling; D055806:Microvessels / Q000378:metabolism*; D051381:Rats; D014471:Umbilical Veins
chemical_list: D005947:Glucose
references.citation: Circulation. 2002 Oct 15;106(16):2067-72
references.pmid: 12379575
references.citation: J Thromb Haemost. 2004 Aug;2(8):1453-9
references.pmid: 15304054
references.citation: N Engl J Med. 2005 Dec 22;353(25):2643-53
references.pmid: 16371630
references.citation: Am J Physiol Endocrinol Metab. 2000 Oct;279(4):E782-90
references.pmid: 11001759
references.citation: Lancet. 1998 Sep 12;352(9131):837-53
references.pmid: 9742976
references.citation: Lancet. 1999 Aug 21;354(9179):617-21
references.pmid: 10466661
references.citation: Br J Pharmacol. 2003 Oct;140(4):681-90
references.pmid: 14504138
references.citation: Diabetes. 2005 Jan;54(1):1-7
references.pmid: 15616004
references.citation: Diabetes. 1997 Dec;46(12):2096-101
references.pmid: 9392502
references.citation: N Engl J Med. 2008 Oct 9;359(15):1577-89
references.pmid: 18784090
references.citation: J Hypertens. 2007 Dec;25(12):2421-5
references.pmid: 17984663
references.citation: N Engl J Med. 2008 Jun 12;358(24):2560-72
references.pmid: 18539916
references.citation: Endocrinology. 2004 Nov;145(11):4934-9
references.pmid: 15284196
references.citation: N Engl J Med. 1993 Sep 30;329(14):977-86
references.pmid: 8366922
references.citation: Life Sci. 2001 Jan 5;68(7):727-37
references.pmid: 11205865
references.citation: Diabetologia. 2004 Nov;47(11):1948-52
references.pmid: 15558232
references.citation: Biochem Biophys Res Commun. 2004 Nov 26;324(4):1204-9
references.pmid: 15504342
references.citation: Nat Med. 2009 Apr;15(4):372-3
references.pmid: 19350008
references.citation: Lab Invest. 2004 Nov;84(11):1451-9
references.pmid: 15448709
references.citation: Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2292-301
references.pmid: 17673705
references.citation: Circ Res. 2006 May 12;98(9):1134-40
references.pmid: 16574902
references.citation: J Clin Invest. 1998 May 1;101(9):1905-15
references.pmid: 9576755
references.citation: Circ Res. 2007 Aug 3;101(3):234-47
references.pmid: 17673684
references.citation: N Engl J Med. 2008 Jun 12;358(24):2545-59
references.pmid: 18539917
references.citation: Immunol Rev. 2007 Aug;218:126-34
references.pmid: 17624949
references.citation: Arterioscler Thromb. 1994 Oct;14(10):1665-73
references.pmid: 7522548
references.citation: J Hypertens. 2008 Mar;26(3):396-8
references.pmid: 18300846
references.citation: Blood. 2004 Jul 15;104(2):402-8
references.pmid: 15044253
references.citation: Nature. 2000 Sep 14;407(6801):233-41
references.pmid: 11001066
references.citation: N Engl J Med. 2007 Apr 12;356(15):1517-26
references.pmid: 17429083
references.citation: Physiol Res. 2004;53(1):77-82
references.pmid: 14984317
references.citation: Trends Endocrinol Metab. 2001 Jul;12(5):225-30
references.pmid: 11397648
references.citation: Eur Heart J. 2007 Apr;28(7):806-13
references.pmid: 17403721
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: FASEB J. 2005 Dec;19(14):2057-9
references.pmid: 16129698
references.citation: Scand J Clin Lab Invest. 2002;62(7):485-93
references.pmid: 12512738
references.citation: Diabetes. 1994 Sep;43(9):1103-7
references.pmid: 7520876
references.citation: FASEB J. 2005 Nov;19(13):1914-6
references.pmid: 16172186
references.citation: J Biol Chem. 1996 May 31;271(22):13094-102
references.pmid: 8662702
references.citation: N Engl J Med. 2009 Jan 8;360(2):129-39
references.pmid: 19092145
references.citation: Diabetes. 2000 Mar;49(3):485-91
references.pmid: 10868972
references.citation: J Pharmacol Exp Ther. 2006 Jul;318(1):53-8
references.pmid: 16595735
references.citation: J Am Coll Cardiol. 2005 May 17;45(10):1563-9
references.pmid: 15893167
references.citation: Am J Physiol Endocrinol Metab. 2001 Jun;280(6):E848-56
references.pmid: 11350766
references.citation: Cell Signal. 2008 Jan;20(1):186-94
references.pmid: 17993261
references.citation: Diabetes. 2008 Jul;57(7):1952-65
references.pmid: 18420487
references.citation: J Hypertens. 2008 Mar;26(3):478-85
references.pmid: 18300858
references.citation: Circulation. 2000 May 16;101(19):2247-51
references.pmid: 10811590
references.citation: Diabetes. 2006 Mar;55(3):774-9
references.pmid: 16505242
references.citation: J Immunol. 1996 Oct 15;157(8):3587-97
references.pmid: 8871659