The leading cause of premature death in diabetic patients is atherosclerotic cardiovascular disease, but mechanisms underlying diabetes-accelerated atherogenesis are not understood. The objective of this project is to characterize lipid signaling mechanisms in diabetic monocytes that migrate into the vascular wall and participate in atherogenesis. These studies may identify events that could be targets for pharmacologic interventions to retard diabetes-associated atherosclerosis. Monocytes are precursor of lipid-laden foam cells in atheroma, and we have found that diabetic monocytes exhibit changes in lipid composition and signaling mechanisms. These include accumulation of lipids derived from intermediates produced by peroxisomes. Our hypothesis is that these changes induce an abnormal activation state of diabetic monocytes that accelerates their entry into the vascular wall, accumulation of lipids, and production of signaling molecules, including cytokines that affect other vascular cells. We postulate that these changes result in part from dysregulation of peroxisomal lipid synthesis by abnormal signaling through peroxisome- proliferator activated receptors (PPAR). This is postulated to cause dysregulation of phospholipases A2 (PLA2) that participate in peroxisomal lipid synthesis and signaling events that control migration and proliferation. Glucose-driven de novo DAG synthesis occurs in cultured macrophages and diabetic vascular tissue. Diabetic monocytes accumulate diacyglycerol (DAG) and exhibit increased phospholipid arachidonate (20:4) and plasmalogen contents similar to those observed in Zucker Diabetic Fatty rat aortae, and these events facilitate PLA2- catalyzed 20:4 release. Mechanisms for altered monocyte lipid composition and enhanced 20:4 release induced by factors in the diabetic milieux will be examined, and peroxisomal contributions to DAG generation will be determined. Functional effects of PLA2-catalyzed 20:4 release on monocyte NADPH oxidase, chemotaxis, and other events will be examined pharmacologically and by molecular biologic methods to manipulate PLA2 isozyme expression. Roles of iPLA2 isozymes in modulating lipid changes in and interactions between blood monocytes and injured vessels wall will be examined, and mice rendered null for iPLA2 isozyme expression will be used to examine iPLA2 participation in atherogenesis.
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