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）：假体移植物被广泛用于血管重建手术中，但其长期通畅受到限制，部分原因是由氧化的低密度脂蛋白（OXLDL）引起的细胞功能改变。我们已经表明：1）移植物质刺激单核细胞在体外氧化LDL，2）该OXLDL抑制内皮细胞（EC）体外迁移（EC）体外迁移，3）外植入的移植物包含的脂质氧化产物比相邻的aorta和4）高胆固醇铅迁移到繁殖中，均高于相邻的aorta。我们还拥有初步数据，即溶血磷脂酰胆碱（Lysopc）是一种脂质氧化产物，占OXLDL的大部分抑制活性，可降低核转录因子过氧化物酶体增殖物激活受体Y（PPARY）的水平，并降低了Ppary Sigands在Lysopc中的迁移。基于这些数据，我们提出了一种假设，即在合成血管移植物中积累的特定脂质氧化产物抑制了PPARY，从而允许持续炎症和产生活性氧（ROS），从而有助于抑制EC迁移，从而限制了Vivo中的prosthetic Grafts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，我们将确定OXLDL和LYSOPC对EC的PPARA和PPARY表达和活性的影响，并探索机制，通过该机制，PPAR配体在存在脂质氧化产物的情况下保留EC的迁移，特别是它们对LysoPC诱导的ROS ROS产生的作用。我们将研究PPAR对体内移植物愈合的影响，比较EPTFE移植物中的PPARA和PPARY表达和兔子中正常主动脉对常规的Chow和高胆固醇饮食的影响，并评估PPARY配体对Eptfe Frafts在这些兔子中Eptfe Grafts中的EC INGROWTH对EC INGROWTH的影响。拟议的研究将研究脂质氧化产物在合成血管移植物的有限内皮化中的作用。研究还将解决PPARY配体在体内促进EC愈合的功效。这将使人们更好地理解脂质在移植失败的病理生物学中的作用，并最终导致促进假体移植物内皮化和延长小直径通道的通畅性的方法。 Lay摘要：我们的研究的目的是更多地了解绕过移植物失败的原因以及预防旁路的方法。具体而言，我们将研究为什么通常将血管排列的细胞无法覆盖合成旁路移植物。