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(申请人提供)：人造移植物在血管重建手术中被广泛使用，但其长期通畅性有限，部分原因是氧化型低密度脂蛋白(OxLDL)引起的细胞功能改变。我们发现：1)移植物材料在体外刺激单核细胞氧化低密度脂蛋白，2)氧化低密度脂蛋白抑制内皮细胞在体外的迁移，3)移植的移植物含有比主动脉近端更多的脂质氧化产物，4)高胆固醇血症导致内皮细胞在移植物上的迁移减少。我们也有初步的数据表明，占oxLDL抑制活性大部分的脂氧化产物溶血磷脂酰胆碱(LysoPC)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配体保护了EC在LysoPC中的迁移。基于这些数据，我们提出一个假设，即在合成血管移植物中积累的特定脂质氧化产物可以抑制PPARy，从而允许持续的炎症和有助于抑制EC迁移的活性氧物种(ROS)的产生，从而限制体内人工血管的内皮化。本项目的目标是确定oxLDL和lysoPC对PPAR表达和活性的影响，以及PPAR在体外和体内对EC迁移的影响。为了验证我们的假设，我们将测定oxLDL和lysoPC对体外培养的EC中PPARa和PPARy表达和活性的影响，并探讨PPAR配体在有脂质氧化产物存在的情况下保护EC迁移的机制，特别是它们对LysoPC诱导的ROS产生的影响。我们将通过比较PPARa和PPARy在正常饮食和高胆固醇饮食下在兔ePTFE移植物和正常主动脉中的表达，探讨PPARs在体内移植物愈合中的作用，并评价PPARy配体对ePTFE移植物内皮细胞生长的影响。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愈合的有效性。这将有助于更好地了解脂质在移植物失败的病理生物学中的作用，并最终找到促进人工移植物内皮化和延长小直径管道通畅的方法。总结：我们研究的目标是更多地了解搭桥术失败的原因和预防方法。具体地说，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。