Aims/hypothesis. Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mech- anisms are poorly understood. We tested the hypothe- sis that insulin increases monocyte-endothelial inter- actions, 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 path- ways, we treated endothelial cells with known pharma- cological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3 ? -kinase (PI3 ? -ki- nase) inhibitor wortmannin (3 × 10 - 8 to 10 - 6 mol/l), in- volved in insulin-induced endothelial nitric oxide syn- thase stimulation, and the p38 mitogen-activated pro- tein (p38MAP) kinase inhibitor SB-203580 (10 - 7 to 2 × 10 - 6 mol/l). We measured adhesion molecule ex- pression 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 ex- pression of intercellular adhesion molecule-1 and E-se- lectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the ab- sence of cytotoxicity, wortmannin significantly poten- tiated 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 indi- cate that insulin promotes VCAM-1 expression in en- dothelial cells through a p38MAP-kinase pathway, am- plified by the PI3 ? -kinase blockage. This could con- tribute to explaining the increased atherosclerosis oc- curring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3 ? -ki- nase pathway. [Diabetologia (2004) 47:532-536]
Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase
Massaro M;
2004
Abstract
Aims/hypothesis. Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mech- anisms are poorly understood. We tested the hypothe- sis that insulin increases monocyte-endothelial inter- actions, 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 path- ways, we treated endothelial cells with known pharma- cological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3 ? -kinase (PI3 ? -ki- nase) inhibitor wortmannin (3 × 10 - 8 to 10 - 6 mol/l), in- volved in insulin-induced endothelial nitric oxide syn- thase stimulation, and the p38 mitogen-activated pro- tein (p38MAP) kinase inhibitor SB-203580 (10 - 7 to 2 × 10 - 6 mol/l). We measured adhesion molecule ex- pression 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 ex- pression of intercellular adhesion molecule-1 and E-se- lectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the ab- sence of cytotoxicity, wortmannin significantly poten- tiated 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 indi- cate that insulin promotes VCAM-1 expression in en- dothelial cells through a p38MAP-kinase pathway, am- plified by the PI3 ? -kinase blockage. This could con- tribute to explaining the increased atherosclerosis oc- curring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3 ? -ki- nase pathway. [Diabetologia (2004) 47:532-536]I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
