De rol van uit de cel afkomstige microdeeltjes bij atherogenese in type 2 diabetes mellitus
01 / 2000 - 01 / 2004
Background: Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular disease (CVD) in type 2 diabetes mellitus (DM). Increased circulating levels of regulatory proteins, which are at least in part derived from endothelial cells, presumably reflect endothelial dysfunction. Endothelial cells as well as blood cells release small membrane vesicles or microparticles (MP). MP promote coagulation and elevated levels of MP are present in the circulation of patients at risk for thromboembolic events and CVD. Moreover, MP are deposited in atherosclerotic plaques and predict myocardial infaction in size. Increased numbers of platelet-derived MP are found in type 2 diabetic patients with dyslipidemia and microvascular complications. Recently, in early uncomplicated type 2 diabetic patients, but not in controls, we found subpopulations of platelet- and leukocyte-derived MP which expose tissue factor (TF), the initiator of coagulation in vivo. The presence of TF-exposing MP significantly correlated with body mass index andinsulin levels. Thus, the cellular origin and antigenic composition of MP in type 2 DM clearly differ from healthy subjects. Hypothesis: We hypothesize that cell-derived MP play a role in the development of atherogenesis in type 2 DM, by exposing mediators such as TF and adhesion molecules, some of which are currently assumed to be (soluble) markers of endothelial dysfunction. We propose that circulating MP reflect diabetes-related abnormalities of the cells of origin and may be related to the severity of vascular damage. In addition, the formation of distinct subpopulations of atherogenic MP may be differentially linked to hyperglycemia, dyslipidemia and insulin resistance. Methods: To this purpose, both in vivo and in vitro studies will be performed. First, from patients with uncomplicated type 2 DM and from those with macrovascular complications and controls, MP will be isolated and characterized with respect to their numbers and antigenic composition. Subpopulations of MP will be related to CVD and the established cardiovascular risk factors. Second, a standardized test meal will be used to study the effect of hyperglycemia and hypertriglyceridemia on MP generation in vivo. Third, the ability of MP isolated from patients in the fasting and postprandial states to trigger thrombin formation and to stimulate production of cytokines and growth factors in cultured human endothelial cells and isolated platelets will be studied. Finally, the effects of environmental stimuli, i.e. those mimicking the diabetic state, such as patient plasma, high glucose, insulin and lipoprotein levels, in the release and composition of cell-derived MP will be studied in vitro using endothelial celis and platelets. Expected results: To gain insight into the pathophysiological mechanisms leading to formation of cell-derived MP and their contribution to the development of atherogenesis in type 2 diabetic patients.