Short-term high glucose exposure induces monocyte-endothelial cells adhesion and transmigration by increasing VCAM-1 and MCP-1 expression in human aortic endothelial cells

Abstract

Acute, short-term hyperglycemia is becoming recognized as an important risk factor for several diseases. In the present study, using human aortic endothelial cells (HAECs), we investigated whether short-term high glucose exposure, either on the scale of hours, could enhance the monocyte adhesion and migration to the subendothelium via increasing expression of adhesion molecules and release of chemotactic factors. HAECs stimulated with 25 mM d(+)glucose (HG) for not more than 12 h, exhibited rapid up-regulation of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein. Although intercellular adhesion molecule-1 (ICAM-1) is considered as a marker of the activation of the atherogenic process, early up-regulation was not observed, and VCAM-1 and MCP-1 protein enhance was sufficient to increase the adhesiveness of human monocytes U-937 to HAECs and their transmigration into the subendothelial space after 4 h HG stimulation; both effects were prevented by interfering with monoclonal antibodies against VCAM-1, CD11b, and MCP-1. An increased intracellular oxidative stress, a translocation of NF-κB to the nucleus and a prevention of adhesion and transmigration of U-937 by interfering with NF-κB inhibitors was also observed after a short HG treatment. Taken together, these results suggest that either acute hyperglycemic spikes could exert an influence on the onset of diabetic complications and on the development of the atherogenic profile on diabetic and non-diabetic subjects.

Introduction

There is increasing evidence that the postprandial state is an important contributing factor to the development of atherosclerosis in diabetic, non-diabetic and non-diabetic critically ill subjects [1], [2], [3]. Chronic hyperglycemia as been postulated to be a cause of microvascular and macrovascular diabetic complications, including atherosclerosis [4], [5]. With regard to infarction, a recent meta-analysis has shown a continuous correlation between glucose serum concentrations and severity of the prognosis even in non-diabetic subjects [6]. Rapid increases in blood glucose concentrations are common and frequent events in the life of non-diabetic and diabetic patients [7]. Despite that, it is surprising how little emphasis researchers have previously put on glycemic spikes as possible contributors to diabetic complications and to complication of different nature in non-diabetic subjects.

The adhesion and migration of circulating monocytes into the subendothelial space is one of the key events in the early stages of atherosclerogenesis [8]. This process is in part regulated by the expression of some adhesion molecules on the surface of endothelial cells (ECAMs), including vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and intercellular adhesion molecule-1 (ICAM-1) and by the release of chemotactic factors including monocyte chemoattractant protein-1 (MCP-1) [9], [10].

Although there are numbers of evidence that underline the effect of chronic high glucose exposure, early damage of human aortic endothelial cells (HAECs) by short-term high glucose stimulation is not fully investigated.

Therefore, our study aims to emphasize the effects of acute hyperglycemia on the development of several health complications, becoming advisable to consider this aspect, the control of hyperglycemic spikes, in the treatment of several complications and diseases.