Hyperketonemia increases monocyte adhesion to endothelial cells and is mediated by LFA-1 expression in monocytes and ICAM-1 expression in endothelial cells

Abstract

Rains JL, Jain SK. Hyperketonemia increases monocyte adhesion to endothelial cells and is mediated by LFA-1 expression in monocytes and ICAM-1 expression in endothelial cells. Am J Physiol Endocrinol Metab 301: E298 -E306, 2011. First published May 3, 2011 doi:10.1152/ajpendo.00038.2011.-Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. The objective of this study was to examine the hypothesis that hyperketonemia increases monocyte-endothelial cell (EC) adhesion and the development of vascular disease in diabetes. Human U937 and THP-1 monocyte cell lines and human umbilical vein endothelial cells (HUVECs) were cultured with acetoacetate (AA) (0 -10 mM) or ␤-hydroxybutyrate (BHB) (0 -10 mM) for 24 h prior to evaluating adhesion and adhesion molecule expression. The results demonstrate a significant (P Ͻ 0.01) increase in both U937 and THP-1 adhesion to HUVEC monolayers treated with 4 mM AA compared with control. Equal concentrations of BHB resulted in similar increases in monocyte-EC adhesion. Similarly, treatments of AA or BHB to isolated monocytes from human blood also show increases in adhesion to endothelial cells. intercellular adhesion molecule-1 (ICAM-1) was significantly increased on the surface of HUVECs and an increase in total protein expression with AA treatment compared with control. The expression level of lymphocyte function-associated antigen-1 (LFA-1) was increased in monocytes treated with AA, and LFA-1 affinity was altered from low to high affinity following treatment with both AA and BHB. Monocyte adhesion could be blocked when cells were preincubated with an antibody to ICAM-1 or LFA-1. Results also show a significant increase in IL-8 and MCP-1 secretion in monocytes and HUVECs treated with 0 -10 mM AA. These results suggest that hyperketonemia can induce monocyte adhesion to endothelial cells and that it is mediated via increased ICAM-1 expression in endothelial cells and increased expression and affinity of LFA-1 in monocytes.intercellular adhesion molecule-1; lymphocyte function-associated antigen-1; ketosis; type 1 diabetes; inflammation; adhesion molecules VASCULAR INFLAMMATION and cardiovascular disease (CVD) are the leading causes of mortality and morbidity among patients with diabetes. Type 1 diabetes (T1D) is associated with increased vascular complications and is considered a proinflammatory condition (8). Studies in the current literature indicate that T1D is associated with increased oxidative stress and increased levels of various inflammatory biomarkers such as CRP, monocyte activity, sICAM, sE-selectin, sP-selectin, and sCD40L (9,10,20). The current literature also contains reports of an increased risk for CVD in T1D (12,29,34). In addition to hyperglycemia, T1D patients frequently experience hyperketonemia due to a state of insulin deficiency. T1D is the most common pathological cause of elevated ketone bodies; however, it has also been shown to coexist with hyperglycemia among older T2D patients and in select minority groups with...

Effect of Hyperketonemia (Acetoacetate) on Nuclear Factor-κB and p38 Mitogen-Activated Protein Kinase Activation Mediated Intercellular Adhesion Molecule 1 Upregulation in Endothelial Cells

“…16 Our previous work has shown that hyperketonemia leads to adhesion molecule expression and adhesion of monocytes to endothelial cells via LFA-1/ICAM-1 interactions. 15 This study also reported that AA induced chemokine monocyte chemoattractant protein-1 (MCP-1) and IL-8 secretion in monocytes and endothelial cells, both of which play a dominant role in atherogenesis processes. 31 The literature suggests that NF-kB plays a major role in regulating the transcription of inflammatory genes whereas MAPKs regulate both the transcription and the stability of mRNA transcripts.…”

“…These results suggest that NF-kB may be the major transcription factor involved in upregulation of other inflammatory biomarkers that have previously been shown to be influenced by hyperketonemic conditions, such as ICAM-1, TNF-a, and IL-6. 15,17,29 Because ICAM-1 is a well-documented NF-kB target gene and is upregulated in inflammatory condition, [35][36][37] it is reasonable to speculate that NF-kB is involved in the regulation of AA-induced ICAM-1 expression. NF-kB is a well-defined redox-sensitive transcription factor.…”

“…15,27 To determine whether ROS and MAPK signaling was involved in the regulation of AA-induced ICAM-1 expression, cells were pretreated with NAC and inhibitors to p38 MAPK (SB203580) or JNK (SP600125), and the surface expression of ICAM-1 was measured using flow cytometry. Figure 4 shows that inhibition of ROS using 3 mM NAC decreased AA-induced ICAM-1 expression to control levels.…”

“…Our previous studies have shown that hyperketonemia increases monocyte adhesion to endothelial cells and is mediated by lymphocyte function-associated antigen 1 (LFA-1) expression in monocytes and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells. 15 Other studies have shown that AA results in oxidative stress that activates extracellular signal-regulated kinase (ERK) and the p38 signaling pathways in hepatocytes. 16,17 No studies in the literature have examined the role of nuclear factor-kB (NF-kB) and mitogen-activated protein kinases (MAPKs) in hyperketonemia-induced adhesion molecule expression.…”

Manganese Supplementation Reduces High Glucose-induced Monocyte Adhesion to Endothelial Cells and Endothelial Dysfunction in Zucker Diabetic Fatty Rats

“…Monocyte-Endothelial Cells Adhesion Assay-Assay was performed as described previously (17). HUVECs were plated and allowed to grow to confluent monolayers.…”