Perturbed postprandial lipoprotine metabolism is considered a contributing factor in premature atherosclerosis and the thrombotic complications of coronary artery disease (CAD). A goal of this proposal is to define specific initiating mechanisms by which abnormal postprandial (pp) lipoprotein metabolism contributes to atherogenesis and thrombosis. Key early events involve functional changes in circulating monocytes and endothelial cells (ECs): increased monocyte adherence to ECs, which precedes formation of fatty streaks, and enhanced expression of tissue factor (TF), which precedes clot formation. Triggering mechanisms are not yet known,but data presented here and in the literature suggest that lipid changes in monocytes and ECs are associated with enhanced monocyte adherence and increased TF activity in both cell types. A potential daily perturbant, which has lacked attention in terms of monocyte and EC function, is abnormal pp lipoprotein metabolism in subjects at increased CAD risk. Both monocytes and ECs are directly exposed to blood and to ppTGRLPs. In other words, we suggest that transient ppTGRLPs may contribute to atherogenesis and thrombosis without entering the arterial wall, a process sometimes considered unlikely for large TGRLP. Indeed, preliminary studies show that circulating monocytes isolated from subjects at risk 4 hours after a defined high-fat meal have increased cholesterol and TG content, increased adhesion to ECs, and increased TF activity. We therefore propose to test the hypothesis that enhanced integration of abnormal ppTGRLP with monocytes and ECs via the MBP 200/235 receptor leads to (1) increased adhesion, due to modulation of activity or expression of cell surface integrins (VLA-4 and LFA-1) on monocytes and their counter receptors (CAM-1, ICAM--1 or E-selectin) on ECs, and (2) increased procoagulant activity in both monocytes and ECs, due to induction or activation of tissue factor (TF). Little is known about the effects of pp lipoprotein metabolism on monocyte-EC adhesion and TF expression and the receptor responsible for ppTGRLP uptake. This proposal directly addresses these gaps and should provide basic cellular and molecular mechanisms to explain the increased CAD risk of certain subjects with abnormal fasting lipoprotein profiles and abnormal postprandial responses.
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