Effect of Lipids on Vascular Graft Healing

脂质对血管移植物愈合的影响

• 批准号: 6923723
• 负责人: Linda M Graham
• 金额: $ 43.29万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923723
• 关键词: acetylcysteine; antihyperlipoproteinemic agent; antioxidants; aorta; atorvastatin; cardiovascular transplantation; cell growth regulation; cell migration; cell proliferation; enzyme activity; free radical oxygen; hypercholesterolemia; immunocytochemistry; laboratory rabbit; lipid metabolism; low density lipoprotein; lysolecithins; oxidation; oxidized lipid; protein kinase C; scanning electron microscopy; transmission electron microscopy; transplant rejection; vascular endothelium; wound healing

DESCRIPTION (provided by applicant): Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited, in part due to altered cell function that could be caused by oxidized low density lipoprotein (oxLDL). We have shown that: 1) graft material stimulates monocytic cells to oxidize LDL in vitro, 2) this oxLDL inhibits endothelial cell (EC) migration in vitro, 3) explanted grafts contain lipid oxidation products, and 4) hypercholesterolemia leads to reduced EC migration onto grafts in rabbits. We also have preliminary data that lysophosphatidylcholine (lysoPC), a lipid oxidation product that accounts for most of oxLDL's inhibitory activity causes an oxidative stress that activates protein kinase C-delta (PKCdelta), and PKCdelta inhibits EC migration. Based on these data, we propose as a hypothesis that specific lipid oxidation products formed within synthetic vascular grafts inhibit EC migration, thereby limiting endothelialization of prosthetic grafts in vivo. The goals of this project are to determine the oxidation pathways active in prosthetic grafts, the mechanism by which oxidized lipids inhibit EC migration, particularly the role of reactive oxygen species (ROS) and activation of PKCdelta, and methods to improve migration. To test our hypothesis, we will identify the mechanism by which lipids in the prosthetic graft are oxidized by assessing molecular markers of specific oxidation pathways. In addition, we will identify the types of lysoPC that are present in synthetic grafts. We will investigate one mechanism by which oxLDL and ROS inhibit EC migration by studying their activation of PKCdelta and the subsequent effects on cytoskeletal proteins. Finally, we will investigate the ability of antioxidants and lipid lowering agents to improve EC migration onto prosthetic grafts implanted in normal and hypercholesterolemic rabbits. The proposed studies will investigate the role of lipids and lipoproteins, and their oxidatively-modified derivatives, in the limited endothelialization of synthetic vascular grafts. Studies will also address the efficacy of antioxidants to control lipid oxidation and promote EC healing. This will lead to a better understanding of the role of lipids in the pathophysiology of graft failure, and ultimately, to methods promoting endothelialization of prosthetic grafts and prolonging patency of small-diameter vascular grafts. I

描述（由申请人提供）： 人工移植物广泛用于血管重建手术，但其长期通畅性有限，部分原因是氧化低密度脂蛋白（oxLDL）可能导致细胞功能改变。我们已经证明：1）移植物材料在体外刺激单核细胞氧化LDL，2）这种oxLDL在体外抑制内皮细胞（EC）迁移，3）移植的移植物含有脂质氧化产物，4）高胆固醇血症导致兔移植物上EC迁移减少。我们也有初步的数据，溶血磷脂酰胆碱（lysoPC），脂质氧化产物，占大部分的oxLDL的抑制活性，导致氧化应激，激活蛋白激酶C-δ（PKC δ），和PKC δ抑制EC迁移。基于这些数据，我们提出了一个假设，即合成血管移植物内形成的特定脂质氧化产物抑制EC迁移，从而限制了体内人工血管移植物的内皮化。该项目的目标是确定假体移植物中活跃的氧化途径、氧化脂质抑制EC迁移的机制，特别是活性氧簇（ROS）和PKC δ激活的作用，以及改善迁移的方法。为了验证我们的假设，我们将通过评估特定氧化途径的分子标志物来确定人工移植物中脂质氧化的机制。此外，我们将确定合成移植物中存在的lysoPC的类型。我们将通过研究oxLDL和ROS对PKC δ的激活以及随后对细胞骨架蛋白的影响来研究oxLDL和ROS抑制EC迁移的机制。最后，我们将研究抗氧化剂和降脂剂的能力，以提高EC迁移到假体移植植入正常和高胆固醇血症兔。拟议的研究将调查的作用，脂质和脂蛋白，及其氧化修饰的衍生物，在有限的内皮化的合成血管移植。研究还将解决抗氧化剂控制脂质氧化和促进EC愈合的功效。这将导致更好地了解脂质在移植失败的病理生理学中的作用，并最终促进人工血管移植物的内皮化和延长小直径血管移植物的通畅性的方法。我