Erk5 and P38 Kinase are Positive Regulators of Insulin and Tnfα - Stimulated Vcam-1 Expression in Rat Aorta Endothelial Cells

Type-2 Diabetes Mellitus (T2DM) is a common disease in the Western world. Hyperinsulinemia, hyperlipidemia and vascular inflammation are among the multitude of dysregulations in the Metabolic X Syndrome. Vascular remodeling, occlusion and rupture are effects of the inflammatory events. These events follow cellular increases in expression of cellular adhesion molecules, adhesion of soluble vascular monocytes, their transmigration to the intima of vessels and eventual expression of inflammatory cytokines. Here we show that hyperphysiological concentrations of insulin and tumor necrosis factor-alpha (TNFα) increase both total and cell surface Vascular Cell Adhesion Molecule-1 (VCAM-1) in rat aorta endothelial cells (RAEC) and these actions are in part regulated by the mitogenactivated protein kinases ERK5 and p38. RAEC transfected with RNAi plasmids of ERK5 and p38 and subsequently stimulated with insulin or TNFα alone or in combination exhibited significant decreases in total and cell surface VCAM-1. Western-blot analysis, flow cytometry and confocal microscopy all indicate that ERK5 and p38 MAP kinases are positive regulators of insulin and TNFα stimulated VCAM-1 expression.