Effect of hyperketonemia on chemokine secretion, adhesion molecule expression, and monocyte adhesion to endothelial cells

Abstract

Frequent episodes of hyperketonemia are associated with higher incidences of vascular disease. We examined the hypothesis that hyperketonemia increases monocyte adhesion to endothelial cells (EC). Human U937 monocytes or THP‐1 monocytes and HUVECs were cultured with AA (0–10 mM) or BHB (0–10 mM) for 24 hours. Results ( ± SE) show that there was significant increase in IL‐8 and MCP‐1 secretion in AA treated THP‐1 and U937 monocytes and HUVECs, however, BHB had no effect. There was a 10.5% ± 0.04 (ns) increase in protein levels of LFA‐1 in 4 mM AA treated U937 monocytes compared to control and a 13% ± 4.3 (p<0.04) increase in surface expression. There was a 21% ± 3.5 (p<0.01) increase in CD14 surface expression on U937 and a 3.9% ± 1.8 (ns) in THP‐1 treated with 4 mM AA compared to control whereas BHB had no effect. Surface ICAM‐1 increased by 23.8% ± 0.02 (p<0.05) and total protein expression by 40% in HUVECs treated with 4 mM AA compared to the control. Results showed a 33.7% ± 2.3 (p<0.01) increase in U937 adhesion and a 23.5% ± 3.8 (p<0.05) increase in THP‐1 adhesion to HUVEC monolayer's treated with 4 mM AA compared to the control. Monocyte adhesion could be blocked by 14% ± 3.6 (p<0.04) when HUVEC's were pre‐incubated with ICAM‐1 antibody. Thus, hyperketonemia increases monocyte adhesion to EC's by upregulation of LFA‐1, CD‐14 and ICAM‐1, which may contribute to the excess vascular disease in diabetes.