Altered metabolism of arachidonic acid in both platelets and endothelial cells may contribute to the pathogenesis of the vascular disease that is a major cause of death and disability in diabetic patients. Our objectives are to examine the sites of regulation of arachidonec acid release from complex lipids, with particular attention to the role of arachidonic acid containing ether lipids, in normal and hyperglycemic settings. We shall study the pathways of arachidonic acid release from phospholipids in endothelial cells to identify which precursor lipids are coupled to specific pathways of arachidonic acid oxygenation. In an animal model of diabetes, we shall study the relative roles of enhanced platelet phospholipase activity compared to increased arachidonic acid content in the increased thromboxane A2 production characteristic of diabetes. We shall undertake, studies of the influence of diabetes on arachidonic acid metabolism at three levels of organization: 1) in broken cells, examining phospholipase A2 and transacylase activity; 2) in cells maintained in culture, examining the regulation of pathways of mobilization of arachidonate and subsequent transformation into active derivatives; 3) in experimental animals, in which diabetes will be induced and platelet metabolism of arachidonic acid will be followed sequentially. The specific hypothesis to be tested are: 1) that arachidonic acid found in diacyl- and that in ether-linked phospholipids is selectively recruited to different oxygenation pathways upon stimulation; 2) that the products of the lipoxygenase pathway may exert feedback regulation on arachidonic acid metabolism in platelets and endothelial cells; 3) that diabetes may alter the extent of lipoxygenase-mediated oxygenation of arachidonic acid and the rates of formation and inactivation of PAF by endothelial cells; and 4) that at least part of the altered formation of eicosanoids in diabetes may reflect altered feedback regulation by lipoxygenase- derived products on arachidonic acid mobilization as well as on cyclooxygenase itself.
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