Abstract 16317: Endothelial Microparticles Derived Under High Glucose Concentrations Promote Vascular Inflammation by Upregulating Adhesion Proteins
Background: Diabetes is a major risk factor for cardiovascular diseases. Circulating endothelial microparticles (EMP) are increased in diabetic patients, but their potential contribution in atherogenesis is unclear. We sought to determine the role of EMP derived under high glucose conditions in the development of atherosclerosis.
Methods and results: EMP were generated from human coronary artery endothelial cells (HCAEC) exposed to high glucose concentrations in order to mimic diabetic conditions. We defined these EMP as "injured" EMP (iEMP) and their effects were compared with EMP generated from untreated HCAEC. In vivo, compared to EMP and vehicle treatment, iEMP injection impaired endothelial function in ApoE-/- mice (p<0.05, n=6-8). Immunofluorescent experiments revealed increased macrophage infiltration and adhesion protein ICAM-1 and VCAM-1 expression in atherosclerotic lesions of iEMP-treated ApoE-/- mice (p<0.05, n=6-8). To investigate the underlying mechanism of iEMP-induced vascular inflammation, in vitro experiments were performed. Interestingly, iEMP, but not EMP, induced upregulation of ICAM-1 and VCAM-1 in target endothelial cells in a time- and dose-dependent manner. Furthermore, iEMP-treatment increased monocyte adhesion on HCAEC compared to EMP-treatment and control. We next investigated how iEMP activate endothelial cells and found that several proinflammatory cytokines are detectable in iEMP. Among those, the levels of TGF-β and IL-8 were significantly higher in iEMP than in EMP. As TGF-β and IL-8 phosphorylate p38 into biologically activate p-p38, expression of p38 activity was analyzed in HCAEC after iEMP stimulation. Time dependent experiments revealed that iEMP induced activation of p38 in endothelial cells within 30 min. Inhibition of p38 activation abrogated iEMP-dependent induction of adhesion proteins and promotion of monocyte adhesion on target cells.
Conclusion: Endothelial microparticles from glucose-treated cells increase vascular inflammation and impair endothelial function. Activation of the endothelium through proinflammatory cytokines in MP might be a possible pathway. These findings provide new insights into the role of microparticles in the pathogenesis of atherosclerosis.
- © 2012 by American Heart Association, Inc.