ARACHIDONIC ACID METABOLISM IN DIABETES

花生四烯酸在血小板和 内皮细胞可能有助于发病机制， 血管疾病是导致死亡和残疾的主要原因， 糖尿病患者 我们的目标是研究 调节花生四烯酸从复合脂质中的释放， 特别注意含有花生四烯酸的作用， 醚脂质，在正常和高血糖设置。 我们将研究 花生四烯酸从磷脂中释放的途径 内皮细胞，以确定哪些前体脂质与 花生四烯酸氧化的特定途径。 动物中 糖尿病模型，我们将研究增强的相对作用， 血小板磷脂酶活性与花生四烯酸 血栓素A2产生增加中的酸含量 糖尿病的特征。 我们将研究糖尿病对 花生四烯酸代谢在三个组织水平： 1)在破碎的细胞中，检测磷脂酶A2和转酰酶 活动; 2)在培养的细胞中，检查 花生四烯酸的动员途径和随后的 转化为活性衍生物; 3)在实验动物中，其中将诱导糖尿病， 将跟踪花生四烯酸的血小板代谢 按顺序 待检验的具体假设为： 1)花生四烯酸存在于二酰基中， 磷脂被选择性地募集到不同的氧合 刺激后的通路; 2)脂氧合酶途径的产物可能发挥 血小板花生四烯酸代谢的反馈调节 和内皮细胞; 3)糖尿病可能会改变脂氧合酶介导的 花生四烯酸的氧化和形成速率， 通过内皮细胞灭活PAF;和 4)至少部分改变了类花生酸的形成， 糖尿病可能反映了脂氧合酶反馈调节的改变， 衍生产品对花生四烯酸动员以及对 环氧合酶本身。

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.