Lipid signaling in diabetic vascular wall cells

糖尿病患者过早死亡的主要原因是动脉粥样硬化性心血管疾病，但糖尿病加速动脉粥样硬化形成的机制尚不清楚。该项目的目的是表征糖尿病单核细胞中迁移到血管壁并参与动脉粥样硬化形成的脂质信号机制。这些研究可能确定可以作为药物干预目标的事件，以延缓糖尿病相关的动脉粥样硬化。单核细胞是动脉粥样硬化中高脂泡沫细胞的前体细胞，我们发现糖尿病单核细胞表现出脂质组成和信号转导机制的改变。这些包括从过氧酶体产生的中间产物中获得的脂类的积累。我们的假设是，这些变化诱导了糖尿病单核细胞的异常激活状态，加速了它们进入血管壁、脂质积累和信号分子的产生，包括影响其他血管细胞的细胞因子。我们推测，这些变化的部分原因是通过PPAR(Peroxisome-Proplator Actiated Receptor，PPAR)的异常信号，导致了过氧酶体脂质合成的失调。这被认为是导致磷脂酶A2(PLA2)的失调，磷脂酶A2参与过氧体脂肪合成和控制迁移和增殖的信号事件。葡萄糖驱动的从头合成DAG发生在培养的巨噬细胞和糖尿病血管组织中。与Zucker糖尿病肥胖大鼠一样，糖尿病大鼠的单核细胞积聚了二酰甘油(DAG)，并表现出磷脂花生四烯酸(20：4)和血浆蛋白原含量的增加，这些事件促进了PLA2催化的20：4的释放。研究糖尿病环境因素引起的单核细胞脂质组成改变和20：4释放增强的机制，并确定过氧化体对DAG生成的贡献。PLA2催化的20：4释放对单核细胞NADPH氧化酶、趋化性和其他事件的功能影响将通过药理学和分子生物学方法来调节PLA2同工酶的表达。将研究iPLA2同工酶在调节血液单核细胞和受损血管壁之间的脂质变化和相互作用中的作用，以及iPLA2同工酶表达缺失的小鼠将被用来研究iPLA2在动脉粥样硬化中的参与。

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.