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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：
8420507
负责人：
Linda M Graham
金额：
$ 43.43万
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：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420507
关键词：
Address Anastomosis - action Angioplasty Animals Aorta Apolipoprotein A-I Area Arterial Injury Arteries Balloon Angioplasty Blood Vessels Bypass Calcium Calcium Channel Calcium ion Calpain Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell membrane Cell physiology Cell surface Cells Cholesterol Cholesterol Esters Complex Cytoskeletal Proteins Data Deposition Development Diet Disease Endothelial Cells Extracellular Matrix Focal Adhesions Functional disorder Goals Growth Healed High Density Lipoproteins Human Hyperlipidemia Hyperplasia Implant In Vitro Infiltration Inflammatory Inflammatory Response Injury Intervention Ion Channel Lead Lipids Lipoproteins Low Density Lipoprotein oxidation Low-Density Lipoproteins Lysophosphatidylcholines Membrane Fluidity Modeling Movement Mus Myosin Light Chain Kinase Nicotinic Acids Operative Surgical Procedures Oryctolagus cuniculus Outcome Pathway interactions Patients Phospholipase Phospholipase C Phosphotransferases Play Production Property Prosthesis Proteins Reactive Oxygen Species Reconstructive Surgical Procedures Research Role Site Structural Protein Surface Testing Time Vascular Graft atherogenesis base cell motility design graft failure graft function graft healing healing hypercholesterolemia improved improved functioning in vivo inhibitor/antagonist injured macrophage migration mimetics mouse model novel strategies oxidation oxidized lipid oxidized low density lipoprotein prevent protein kinase C-delta public health relevance receptor src-Family Kinases therapy development

项目摘要

DESCRIPTION (provided by applicant): Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited by their thrombogenicity and the development of intimal hyperplasia. Oxidized LDL and lysophosphatidylcholine (lysoPC), a product of LDL oxidation, accumulate in grafts and alter cell function. The long-term goal of our research is to improve the patency of vascular grafts by promoting endothelial cell (EC) healing of graft surfaces. LysoPC inhibits EC migration in vitro, and hypercholesterolemia reduces EC migration into injured arteries and onto grafts. Old and lysoPC increase cellular production of reactive oxygen species, increase cell membrane fluidity, and open ion channels. These effects can inhibit EC migration. Specifically, lysoPC activates a canonical transient receptor potential (TRPC) ion channel, TRPC6, which opens TRPC5 through a unique TRPC activation cascade, leading to a prolonged rise in intracellular free calcium ion concentration ([Ca2+]i). Increased [Ca2+]i inhibits EC migration by activation of calpains that breakdown cytoskeletal proteins essential for migration. This proposal addresses the hypothesis that lipid oxidation products formed within synthetic vascular grafts inhibit their EC migration, in part through activation of TRPC6 and TRPC5 channels, and thereby limit endothelialization of grafts in vivo. The goals of this project are to identify mechanisms by which lipid oxidation products activate TRPC6 and TRPC5 channels and identify ways to counteract this. To accomplish these goals, the mechanism by which lipid oxidation products activate TRPC6, specifically the roles of Src kinases and phospholipase C-31, will be explored. In addition, and the mechanism by which TRPC6 activates TRPC5 will be studied, focusing on the role of intracellular calcium and myosin light chain kinase. The role of reactive oxygen species and changes in membrane fluidity in these actions will also be explored. Finally, the ability of an apoA-I mimetic or HDL, which we have shown to block the TRPC6-TRPC5 activation cascade in vitro, to improve EC migration in areas of arterial injury in mice and onto prosthetic grafts implanted in normal and hypercholesterolemic rabbits will be assessed. The proposed studies will investigate a mechanism by which lipid oxidation products limit EC healing of vascular injuries and synthetic vascular grafts. Studies will also address the ability of HDL to promote EC healing. These studies will lead to a better understanding of the role of lipids in the pathophysiology of graft failure, and provide impetus for development of TRPC6 channel inhibitors or agents that interrupt the TRPC6- TRPC5 activation cascade. These mechanism-based therapies will promote endothelial healing of angioplasty sites and prosthetic grafts to prolong their patency for the benefit of all people undergoing cardiovascular interventions.

描述（由申请人提供）：人工血管移植物广泛用于血管重建手术，但其长期通畅性受到血栓形成和内膜增生的限制。氧化的LDL和溶血磷脂酰胆碱（lysoPC），LDL氧化的产物，在移植物中积累并改变细胞功能。我们研究的长期目标是通过促进移植物表面的内皮细胞（EC）愈合来改善血管移植物的通畅性。LysoPC在体外抑制EC迁移，高胆固醇血症减少EC迁移到受损动脉和移植物上。Old和lysoPC增加活性氧的细胞产生，增加细胞膜流动性，并打开离子通道。这些作用可以抑制EC迁移。具体而言，lysoPC激活典型瞬时受体电位（TRPC）离子通道TRPC 6，TRPC 6通过独特的TRPC激活级联反应打开TRPC 5，导致细胞内游离钙离子浓度（[Ca 2 +]i）延长升高。增加的[Ca 2 +]i通过激活钙蛋白酶来抑制EC迁移，钙蛋白酶分解迁移所必需的细胞骨架蛋白。这一提议解决了合成血管移植物内形成的脂质氧化产物部分通过TRPC 6和TRPC 5通道的激活抑制其EC迁移，从而限制体内移植物内皮化的假设。该项目的目标是确定脂质氧化产物激活TRPC 6和TRPC 5通道的机制，并确定抵消这种机制的方法。为了实现这些目标，脂质氧化产物激活TRPC 6的机制，特别是Src激酶和磷脂酶C-31的作用，将进行探索。此外，TRPC 6激活TRPC 5的机制将被研究，重点是细胞内钙和肌球蛋白轻链激酶的作用。在这些行动中的活性氧和膜流动性的变化的作用也将进行探讨。最后，将评估apoA-I模拟物或HDL（我们已经证明其在体外阻断TRPC 6-TRPC 5活化级联）改善小鼠动脉损伤区域中的EC迁移和移植到正常和高胆固醇血症兔中的假体移植物上的EC迁移的能力。拟议的研究将调查脂质氧化产物限制血管损伤和合成血管移植物EC愈合的机制。研究还将解决HDL促进EC愈合的能力。这些研究将导致更好地理解脂质在移植失败的病理生理学中的作用，并为开发TRPC 6通道抑制剂或中断TRPC 6-TRPC 5激活级联的药物提供动力。这些基于机制的治疗将促进血管成形术部位和假体移植物的内皮愈合，以延长其通畅性，从而使所有接受心血管介入治疗的人受益。