Aims/hypothesis. Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mechanisms are poorly understood. We tested the hypothesis that insulin increases monocyte-endothelial interactions, which are implicated in atherosclerosis. Methods. We treated human umbilical vein endothelial cells with insulin (10(-10) to 10(-7) mol/l) for 0 to 24 h. To dissect potentially implicated signal transduction pathways, we treated endothelial cells with known pharmacological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3'-kinase (PI3'-kinase) inhibitor wortmannin (3x10(-8) to 10(-6) mol/l), involved in insulin-induced endothelial nitric oxide synthase stimulation, and the p38 mitogen-activated protein (p38MAP) kinase inhibitor SB-203580 (10(-7) to 2x10(-6) mol/l). We measured adhesion molecule expression by cell surface enzyme immunoassays and U937 monocytoid cell adhesion in rotational adhesion assays. Results. At pathophysiological concentrations (10(-9) to 10(-7) mol/l), insulin concentration-dependently induced vascular cell adhesion molecule (VCAM)-1 (average increase: 1.8-fold) peaking at 16 h. By contrast, the expression of intercellular adhesion molecule-1 and E-selectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the absence of cytotoxicity, wortmannin significantly potentiated the effect of insulin alone on VCAM-1 surface expression and monocytoid cell adhesion, whereas SB-203580 (10(-6) mol/l) completely abolished such effects. Conclusions/interpretation. These observations indicate that insulin promotes VCAM-1 expression in endothelial cells through a p38MAP-kinase pathway, amplified by the PI3'-kinase blockage. This could contribute to explaining the increased atherosclerosis occurring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3'-kinase pathway.
|Autori:||Madonna, R; Pandolfi, A; Massaro, M; Consoli, A; DE CATERINA, R.|
|Titolo:||Insulin enhances vascular adhesion molecule (VCAM-1) expression in human cultured endothelial cells through a pro-atherogenic p38MAP-kinase mediated pathway|
|Anno del prodotto:||2004|
|Digital Object Identifier (DOI):||10.1007/s00125-004-1330-x|
|Appare nelle tipologie:||1.1 Articolo in rivista|