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

Abstract

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 (3×10 −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 2×10 −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. [Diabetologia (2004) Macro-and microvascular complications are the major causes of morbidity and mortality in Type 1 and Type 2 diabetes [1]. The pathogenesis of accelerated atherosclerosis in diabetes is not known, but several mechanisms have been implicated. Clinical and epidemiological studies have shown associations between hyperinsulinaemia, accompanying states of insulin resistance, and cardiovascular disease. These are partly independent of related risk factors like hypertriglyceridaemia, low HDL concentrations and hypertension [1]. Compensatory hyperinsulinaemia resulting from insulin resistance increases the production of plasminogen activator inhibitor-1 and various growth

Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity

“…Thus, TNF-a (2), interleukin-1 (IL-1) (9), IL-4 (10), and peroxisome proliferatoractivated receptor (PPAR) agonists (11) upregulate the synthesis, and interestingly insulin decreases the production (2). This direct effect of insulin on vascular cells is in agreement with other insulin effects concerning both NO synthesis, vasomotoric response (12), expression of adhesion molecules (13), matrix synthesis (14,15), and calcifications (16,17). The understanding of insulin effects in vascular cells is important, since it is not known whether hyperinsulinism or lack of insulin effects in some pathways are prevailing in type 2 diabetes (18,19).…”

“…Moreover, there was no difference in the OPG fold change between obese non-diabetic subjects and patients with type 2 diabetes despite a significantly lower insulin-stimulated GDR in the diabetic group. Thus, the observed effects on plasma OPG could relate to direct effects of insulin on vascular cells, which previously has been observed in a series of both in vivo (12) and in vitro studies (2,(13)(14)(15)41). As the effects of insulin on the vasculature are different from metabolic effects in muscle, fat, and liver, and also have a different timing, the lack of observed correlations are not surprising.…”

Crimean-Congo Hemorrhagic Fever Virus Activates Endothelial Cells

“…VCAM1 and E-selectin transcript levels were also upregulated at the same level as ICAM1, yet this could not be verified by cell surface studies by EIA. This could reflect a technical insensitivity of the EIA method, though the method has been used successfully in other studies to detect cell adhesion molecules on the cell surface (10,18,24).…”

Selective Insulin Resistance Affecting Nitric Oxide Release But Not Plasminogen Activator Inhibitor-1 Synthesis in Fibroblasts From Insulin-Resistant Individuals

“…In vascular wall cells, insulin has been shown to be able to increase leukocytes adhesion molecule expression, 7 endothelin synthesis, 8 vascular smooth cells migration, 6 and PAI-1 transcription and release. 9 All these effects can be considered as proatherogenic.…”

“…Because insulin can activate several processes potentially dangerous for the vascular wall, hyperinsulinemia might contribute to the high cardiovascular risk associated with the syndrome. [1][2][3][4][5] As a matter of fact, insulin promotes vascular smooth muscle cells migration, 6 enhances leukocyte adhesion molecules expression, 7 stimulates endothelin 8 and plasminogen activator inhibitor-1 (PAI-1) 9 -11 synthesis and expression. However, several insulin effects could be considered protective for the vessel wall and thus anti-atherogenic; for instance, insulin inhibits platelet aggregation 12 and stimulates nitric oxide (NO) release.…”