Effect of Oxidized Lipids on Endothelial Migration and Vascular Graft Healing

氧化脂质对内皮迁移和血管移植物愈合的影响

• 批准号: 7328918
• 负责人: Michael Aaric Rosenbaum
• 金额: $ 4.96万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328918
• 关键词: Accounting; Acute; Address; Affect; Agonist; Antioxidants; Aorta; Area; Arterial Injury; Binding; Blood Vessels; Bypass; Calcium Channel; Caliber; Cell Proliferation; Cell physiology; Cells; Data; Deposition; Development; Diet; Disruption; Down-Regulation; Endothelial Cells; Environment; Extracellular Matrix; Focal Adhesions; Foreign Bodies; Functional disorder; Gene Expression; Goals; Healed; Human; Hyperplasia; In Vitro; Infiltration; Inflammation; Injury; Laboratories; Lead; Learning; Ligands; Lipids; Literature; Low Density Lipoprotein oxidation; Lysophosphatidylcholines; Membrane Fluidity; Methods; Modification; NAD(P)H oxidase; Nuclear; Oral; Oryctolagus cuniculus; Oxidative Stress; Peroxisome Proliferator-Activated Receptors; Phospholipids; Process; Production; Property; Prosthesis; Reactive Oxygen Species; Reconstructive Surgical Procedures; Research; Role; Smooth Muscle Myocytes; System; Testing; Transplanted tissue; Vascular Graft; base; cell motility; cytokine; graft failure; graft healing; healing; hypercholesterolemia; improved; in vivo; lipid metabolism; low density lipoprotein inhibitor; macrophage; migration; oxidation; oxidized lipid; oxidized low density lipoprotein; prevent; protein kinase C-delta; receptor expression; transcription factor

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 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 significantly more lipid oxidation products than the adja- cent aorta, 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, decreases the level of the nuclear transcription factor peroxisome proliferator- activated receptor y (PPARy), and that PPARy ligands preserve EC migration in lysoPC. Based on these data, we propose as a hypothesis that specific lipid oxidation products that accumulate within synthetic vascular grafts inhibit PPARy allowing continued inflammation and production of reactive oxygen species (ROS) contributing to the inhibition of EC migration, thereby limiting endothelialization of prosthetic grafts in vivo. The goals of this project are to determine the effect of oxLDL and lysoPC on PPAR expression and activity and the effect of PPARs on EC migration in vitro and in vivo. To test our hypothesis, we will determine the effect of oxLDL and lysoPC on PPARa and PPARy expression and activity in EC in vitro and explore mechanisms by which PPAR ligands preserve EC migra- tion in the presence of lipid oxidation products, specifically their effect on lysoPC-induced ROS production. We will investigate the effect of PPARs on graft healing in vivo, comparing PPARa and PPARy expression in ePTFE grafts and normal aorta in rabbits on regular chow and hypercholesterolemic diets, and assess the effect of PPARy ligand on EC ingrowth in ePTFE grafts in these rabbits. The proposed studies will investigate the role of lipid oxidation products in the limited endothelialization of synthetic vascular grafts. Studies will also address the efficacy of PPARy ligands to promote EC healing in vivo. This will lead to a better understanding of the role of lipids in the pathobiology of graft failure, and ultimately, to methods promoting endothelialization of prosthetic grafts and prolonging patency of small- diameter conduits. Lay summary: The goal of our research is to learn more about why bypass grafts fail and ways to prevent it. Specifically, we will study why the cells that normally line blood vessels fail to cover synthetic bypass grafts.

描述（由申请人提供）：假体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）引起的细胞功能改变。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）外植移植物比邻近主动脉含有明显更多的脂质氧化产物，4）高胆固醇血症导致兔子移植物上的EC迁移减少。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，负责 oxLDL 的大部分抑制活性）降低了核转录因子过氧化物酶体增殖物激活受体 y (PPARy) 的水平，并且 PPARy 配体保留了 lysoPC 中的 EC 迁移。基于这些数据，我们提出一个假设，即合成血管移植物内积累的特定脂质氧化产物会抑制 PPARy，从而导致持续的炎症和活性氧 (ROS) 的产生，从而抑制 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 oxLDL 和 lysoPC 对 PPAR 表达和活性的影响以及 PPAR 对体外和体内 EC 迁移的影响。为了检验我们的假设，我们将在体外确定 oxLDL 和 lysoPC 对 EC 中 PPARa 和 PPARy 表达和活性的影响，并探索 PPAR 配体在脂质氧化产物存在下保护 EC 迁移的机制，特别是它们对 lysoPC 诱导的 ROS 产生的影响。我们将研究 PPARs 对体内移植物愈合的影响，比较常规饮食和高胆固醇饮食的家兔 ePTFE 移植物和正常主动脉中 PPARa 和 PPARy 的表达，并评估 PPARy 配体对这些家兔 ePTFE 移植物中 EC 向内生长的影响。拟议的研究将调查脂质氧化产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 PPARγ 配体促进 EC 体内愈合的功效。这将导致更好地理解脂质在移植失败的病理学中的作用，并最终导致促进假体移植物内皮化和延长小直径导管通畅的方法。简单总结：我们研究的目标是更多地了解搭桥移植失败的原因以及预防方法。具体来说，我们将研究为什么正常排列血管的细胞无法覆盖合成旁路移植物。