leukotriene-b4 and Diabetes-Mellitus

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Diabetes Mellitus; Glucocorticoids; Humans; Hypertension; Leukotriene B4; Lipoxygenase; Membrane Lipids; Organ Specificity; Phospholipases; Plants; Prostaglandin-Endoperoxide Synthases; Prostaglandins; SRS-A; Thrombosis; Thromboxanes

Circulating endothelial progenitor cells (EPCs) are recruited from the blood system to sites of ischemia and endothelial damage, where they contribute to the repair and development of blood vessels. Since numerous eicosanoids including leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) have been shown to exert potent pro-inflammatory activities, we examined their levels in chronic diabetic patients with severe cardiac ischemia in conjunction with the level and function of EPCs.. Lipidomic analysis revealed a diabetes-specific increase (p<0.05) in inflammatory and angiogenic eicosanoids including the 5-lipoxygenase-derived LTB (4.11±1.17 vs. 0.96±0.27 ng/ml), the lipoxygenase/CYP-derived 12-HETE (117.08±35.05 vs. 24.34±10.03 ng/ml), 12-HETrE (17.56±4.43 vs. 4.15±2.07 ng/ml), and the CYP-derived 20-HETE (0.32±0.04 vs. 0.06±0.05 ng/ml) the level of which correlated with BMI (p=0.0027). In contrast, levels of the CYP-derived EETs were not significantly (p=0.36) different between these two groups. EPC levels and their colony-forming units were lower (p<0.05) with a reduced viability in diabetic patients compared with non-diabetics. EPC function (colony-forming units (CFUs) and MTT assay) also negatively correlated with the circulating levels of HgA1C.. This study demonstrates a close association between elevated levels of highly pro-inflammatory eicosonoids, diabetes and EPC dysfunction in patients with cardiac ischemia, indicating that chronic inflammation impact negatively on EPC function and angiogenic capacity in diabetes.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; AC133 Antigen; Aged; Antigens, CD; Body Mass Index; Cell Survival; Chromatography, Liquid; Diabetes Mellitus; Eicosanoids; Endothelial Cells; Female; Flow Cytometry; Glycoproteins; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipids; Male; Middle Aged; Myocardial Ischemia; Peptides; Stem Cells; Tandem Mass Spectrometry; Vascular Endothelial Growth Factor Receptor-2

Inexplicable controversies with regard to possible functional defects of neutrophilic polymorphonuclear leukocytes (PMNs) in diabetes persist. The purpose of the present study was to elucidate the relative effectiveness of several PMN agonists in stimulating lysosomal-enzyme secretion and leukotriene (LT) B(4) production by PMNs isolated from diabetic subjects. Formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) induced significantly less lysosomal-enzyme secretion and LTB(4) production in diabetic-subject PMNs than in normal-subject PMNs. It is surprising that PMNs from these same diabetic subjects responded normally after stimulation with A23187, serum-opsonized zymosan, or phorbol myristate acetate. The in vitro responsiveness of PMNs stimulated with fMLP or PAF was inversely correlated with indices of in vivo glycemic control (fasting plasma glucose and glycated-hemoglobin levels). In combination, these results indicate that hyperglycemia is associated with sustained decreases in PMN function but only in response to agonists that initiate stimulus-response coupling via G-protein-coupled receptors. This agonist-selective reduction in PMN responsiveness may contribute to the compromised host defense associated with sustained hyperglycemia in diabetes.

Topics: Adult; Blood Glucose; Calcimycin; Cells, Cultured; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hyperglycemia; Leukotriene B4; Lysosomes; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Activation; Neutrophils; Platelet Activating Factor; Tetradecanoylphorbol Acetate; Zymosan