Inflammation Determines the Pro-Adhesive Properties of High Extracellular D-Glucose in Human Endothelial Cells In Vitro and Rat Microvessels In Vivo

Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
PLoS ONE (Impact Factor: 3.53). 04/2010; 5(4):e10091. DOI: 10.1371/journal.pone.0010091
Source: PubMed

ABSTRACT 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.
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.
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.

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    • "However, there is circumstantial evidence from in vivo studies both in animals and humans that the endothelium is particularly sensitive to changes in glucose concentrations. Investigators have evaluated the effects of acute (≤ 12 h) glucose administration on leukocyte adhesion to microvascular ECs in rodents using intravital microscopy and found evidence of increased leukocyte rolling and adhesion to microvessels in the absence (Booth et al., 2002) or presence of co-administered IL-1β or TNF-α (Azcutia et al., 2010a). The effects of elevated glucose in these studies were most likely mediated by increased expression of the adhesion molecules P-selectin, VCAM-1, and ICAM-1, through pathways mediated by PKC and increased oxidative stress and/or activation of the NF-κB pathway (Booth et al., 2002; Azcutia et al., 2010b). "
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