Effect of Lipids on Vascular Graft Healing

脂质对血管移植物愈合的影响

基本信息

批准号：
7274799
负责人：
Linda M Graham
金额：
$ 43.16万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-01 至 2009-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7274799
关键词：
Abbreviations Accounting Acetylcysteine Actinin Address Antioxidants Aorta Appendix Biological Markers Bite Blood Vessels Calcium Channel Caliber Cardiovascular Diseases Cell Proliferation Cell membrane Cell physiology Cell surface Cells Chemotactic Factors Cholesterol Critical Pathways Cytoskeletal Proteins Data Deposition Development Diet Diet Modification Disruption Endothelial Cells Environment Extracellular Matrix Focal Adhesions Foreign Bodies Functional disorder Goals Healed Human Hyperlipidemia Hyperplasia Implant In Vitro Intervention Lead Lipids Lipoproteins Low Density Lipoprotein oxidation Low-Density Lipoproteins Lysophosphatidylcholines Methods Mitogens Modeling Oral Oryctolagus cuniculus Oxidants Oxidative Stress Pathway interactions Patients Phosphorylation Play Probucol Process Production Progress Reports Property Prosthesis Protein Kinase C Alpha Reactive Oxygen Species Reconstructive Surgical Procedures Risk Factors Role Smooth Muscle Myocytes Testing Transplanted tissue Vascular Graft atorvastatin base cell motility delta protein fluidity graft failure graft healing healing hypercholesterolemia improved in vivo low density lipoprotein inhibitor macrophage migration monocyte oxidation oxidized lipid oxidized low density lipoprotein protein kinase C-delta stress activated protein kinase syndecan syndecan-4

项目摘要

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) 外植移植物含有脂质氧化产物，4) 高胆固醇血症导致 EC 迁移减少到兔子的移植物上。我们还有初步数据表明，溶血磷脂酰胆碱 (lysoPC)（一种脂质氧化产物，占 oxLDL 抑制活性的大部分）会引起氧化应激，从而激活蛋白激酶 C-delta (PKCdelta)，而 PKCdelta 会抑制 EC 迁移。基于这些数据，我们提出一个假设：合成血管移植物内形成的特定脂质氧化产物抑制EC迁移，从而限制体内假体移植物的内皮化。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 (ROS) 的作用和 PKCdelta 的激活，以及改善迁移的方法。为了检验我们的假设，我们将通过评估特定氧化途径的分子标记来确定假体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 类型。我们将通过研究 oxLDL 和 ROS 对 PKCdelta 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 迁移的一种机制。最后，我们将研究抗氧化剂和降脂剂改善 EC 迁移到植入正常和高胆固醇血症兔子的假体移植物上的能力。拟议的研究将调查脂质和脂蛋白及其氧化修饰衍生物在合成血管移植物的有限内皮化中的作用。研究还将探讨抗氧化剂控制脂质氧化和促进内皮细胞愈合的功效。这将有助于更好地了解脂质在移植物失败的病理生理学中的作用，并最终找到促进假体移植物内皮化和延长小直径血管移植物通畅的方法。我