Probucol restores the defective leukocyte–endothelial interaction in experimental diabetes (original) (raw)
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Diabetes/Metabolism Research and Reviews, 2003
Background Defective leukocyte-endothelial interactions are observed in experimental diabetes and may reduce the capacity to mount an adequate inflammatory response. The present study investigated the effect of ascorbic acid, an inhibitor of free radical and glycated protein formation as well as an aldose reductase inhibitor, on leukocyte-endothelial interaction in alloxan-diabetic rats.
Influence of tolrestat on the defective leukocyte–endothelial interaction in experimental diabetes
European Journal of Pharmacology, 2000
One of the most devastating secondary complications of diabetes is the blunted inflammatory response that becomes evident even in the very early stages of poorly controlled diabetes mellitus. While the etiology of this diminished response is not clearly understood, it has been linked to a decrease in the respiratory burst of neutrophils, as well as a decrease in microvessel response to inflammatory mediators and defective leukocyte-endothelial interactions. Using video microscopy to visualize vessels of the internal spermatic fascia, we have characterized leukocyte-endothelial interactions in alloxan-induced diabetic and in galactosemic rats by quantitating the number of leukocytes rolling along the venular endothelium and the number of leukocytes sticking to the vascular wall after topical application of Ž . Ž . zymosan-activated plasma or leukotriene B 1 ngrml , as well as after the application of a local irritant stimulus carrageenan, 100 mg . 4 We observed that while 33 days of alloxan-induced diabetes or 7 days of galactosemia had no effect on total or differential leukocyte Ž . counts and on the wall shear rate, both treatments significantly P -0.001 reduced the number of leukocytes rolling along the venular endothelium by about 70% and the number of adhered leukocytes in postcapillary venules by 60%. These effects were not observed in diabetic and galactosemic animals treated with an aldose reductase inhibitor. The results suggest that impaired leukocyte-endothelial cell interactions are a consequence of an enhanced flux through the polyol pathway. q 0014-2999r00r$ -see front matter q 2000 Elsevier Science B.V. All rights reserved.
Asian Biomed, 2010
Endothelial dysfunction has been documented as the key process of both macro-and microangiopathy in diabetes mellitus. The development of endothelial dysfunction can be characterized by both impairment of vasorelaxation and increased expression of adhesion molecules. The increase in reactive oxygen species (ROS), subsequently produced from long-term hyperglycemia, was suggested as a major underlying cause of diabetic-induced endothelial dysfunction [1-3]. The interaction between leukocytes and endothelium is one of the markers for diabetesinduced endothelial dysfunction. Interestingly, our previous studies in diabetic rats have shown that vitamin C supplementation could reduce leukocyte-endothelial cell interactions in both experimental models of long-term preventive and early phase reversal trials [4, 5].
Attenuation of leukocyte-endothelium interaction by antioxidant enzymes
Free Radical Biology and Medicine, 2003
This report assessed the effect of overexpressing Cu,Zn superoxide dismutase (SOD) and/or catalase on the interaction of mononuclear cells (MNCs) and endothelial cells (ECs). ECs were obtained from the aorta of wild-type mice and transgenic mice overexpressing Cu,ZnSOD and/or catalase. MNCs were obtained from wild-type mice. Treatment of wild-type ECs with CuSO 4 -oxidized low-density lipoprotein (oxLDL) significantly elevated the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and increased the adherence of MNCs. Overexpression of Cu,ZnSOD and/or catalase in ECs attenuated the adherence of MNCs and the expression of cell adhesion molecules induced by oxLDL. For example, ECs overexpressing Cu,ZnSOD and/or catalase showed significantly less expression of VCAM-1 and ICAM-1 and less number of adherent MNCs than wild-type ECs. Moreover, ECs overexpressing Cu,ZnSOD and catalase in combination showed significantly less expression of VCAM-1 and ICAM-1 and less number of adherent MNCs than those overexpressing either Cu,ZnSOD or catalase alone. These results suggest that combinational overexpression of Cu,ZnSOD and catalase can reduce the expression of cell adhesion molecules and inhibit the adherence of leukocyte to ECs more efficiently than overexpression of Cu,ZnSOD or catalase alone.
Minalrestat and leukocyte migration in diabetes mellitus
Diabetes/Metabolism Research and Reviews, 2003
Background We recently demonstrated that aldose reductase inhibition was effective in restoring the reduced migratory capacity of leukocytes in diabetic rats. To investigate the mechanism(s) involved in the restoring effect, we used minalrestat, an aldose reductase inhibitor.
Journal of Clinical Investigation, 1998
We addressed the role of hyperglycemia in leukocyte-endothelium interaction under flow conditions by exposing human umbilical vein endothelial cells for 24 h to normal (5 mM), high concentration of glucose (30 mM), advanced glycosylation end product-albumin (100 g/ml), or hyperglycemic (174-316 mg/dl) sera from patients with diabetes and abnormal hemoglobin A 1c (8.1 Ϯ 1.4%). At the end of incubation endothelial cells were perfused with total leukocyte suspension in a parallel plate flow chamber under laminar flow (1.5 dyn/cm 2 ). Rolling and adherent cells were evaluated by digital image processing. Results showed that 30 mM glucose significantly ( P Ͻ 0.01) increased the number of adherent leukocytes to endothelial cells in respect to control (5 mM glucose; 151 Ϯ 19 versus 33 Ϯ 8 cells/mm 2 ). A similar response was induced by endothelial stimulation with IL-1  , here used as positive control (195 Ϯ 20 cells/mm 2 ). The number of rolling cells on endothelial surface was not affected by high glucose level. Stable adhesion of leukocytes to glucosetreated as well as to IL-1  -stimulated endothelial cells was preceded by short interaction of leukocytes with the endothelial surface. The distance travelled by leukocytes before arrest on 30 mM glucose, or on IL-1  -treated endothelial cells, was significantly ( P Ͻ 0.01) higher than that observed for leukocytes adhering on control endothelium (30 mM glucose: 76.7 Ϯ 3.5; IL1  : 69.7 Ϯ 4 versus 5 mM glucose: 21.5 Ϯ 5 m). Functional blocking of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 on endothelial cells with the corresponding mouse mAb significantly inhibited glucose-induced increase in leukocyte adhesion (67 Ϯ 16, 83 Ϯ 12, 62 Ϯ 8 versus 144 Ϯ 21 cells/ mm 2 ). Confocal fluorescence microscopy studies showed that 30 mM glucose induced an increase in endothelial surface expression of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1. Electro-phoretic mobility shift assay of nuclear extracts of human umbilical vein endothelial cells (HUVEC) exposed for 1 h to 30 mM glucose revealed an intense NF-kB activation. Treatment of HUVEC exposed to high glucose with the NF-kB inhibitors pyrrolidinedithiocarbamate (100 M) and tosyl-phe-chloromethylketone (25 M) significantly reduced ( P Ͻ 0.05) leukocyte adhesion in respect to HUVEC treated with glucose alone. A significant ( P Ͻ 0.01) inhibitory effect on glucose-induced leukocyte adhesion was observed after blocking protein kinase C activity with staurosporine (5 nM). When HUVEC were treated with specific antisense oligodesoxynucleotides against PKC ␣ and PKC ⑀ isoforms before the addition of 30 mM glucose, a significant ( P Ͻ 0.05) reduction in the adhesion was also seen. Advanced glycosylation end product-albumin significantly increased the number of adhering leukocytes in respect to native albumin used as control (110 Ϯ 16 versus 66 Ϯ 7, P Ͻ 0.01). Sera from diabetic patients significantly ( P Ͻ 0.01) enhanced leukocyte adhesion as compared with controls, despite normal levels of IL-1  and TNF ␣ in these sera.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2002
Objective-We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. Methods and Results-Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (PϽ0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (Pϭ0.03). Conclusions-Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.