The Role of Tenascin in Neointimal Formation

腱蛋白在新内膜形成中的作用

• 批准号: 7406759
• 负责人: Prediman Krishan Shah
• 金额: $ 37.87万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406759
• 关键词: Ablation; Active Sites; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Arteries; Blood Vessels; Breeding; C57BL/6 Mouse; Cell Communication; Cell Culture System; Cells; Chemotaxis; Chronic; Complex; Data; Development; Diet; Disease; Embryonic Development; Employee Strikes; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Eotaxin; Extracellular Matrix Proteins; Fatty acid glycerol esters; Genetic; Genotype; Goals; Hematopoietic; Hyperlipidemia; Hyperplasia; Injury; Investigation; Knockout Mice; Lesion; Leukocytes; Maps; Mediating; Molecular; Mus; Plasma; Role; Site; Tenascin; Testing; Tissues; Tunica Adventitia; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Week; base; beta-Chemokines; cis acting element; feeding; in vivo; injured; mast cell; monocyte; promoter

DESCRIPTION (provided by applicant): Previous investigations by us and others have used a cell culture system to establish the vascular function of TN. We have now extended these observations in vivo to test the hypothesis that the genetic deletion of TN in the apo E-/- background might modify neointimal hyperplasia in an injured artery, and in atherosclerotic lesions. TN/E-mice developed atherosclerotic lesions one-week after being fed on a high fat diet. This lesion development was more rapid and more complex than was observed with Apo E mice. Concomitantly, VCAM- 1 expression was detected in the TN/E group alone. FACS analysis revealed that the VCAM-1 expression level in TN/E-derived endothelial cells was markedly higher than that from apo E mice. Finally, TN was found to down-regulate VCAM-1 promoter activity when induced by TNF-a in endothelial cells. These data suggest that TN deficiency promotes leukocyte/endothelial cell interaction. In addition to the rapid development of plaque, chronic hyperlipidemia in TN/E mice resulted in the formation of unstable plaques. The antibody array and ELISA analyses of chronic hyperlipidemic plasma from the two mouse genotypes showed that eotaxin, a CC chemokine, is selectively upregulated by 4- to 5-fold in the TN/E groups when compared to apo E mice. Furthermore, there was an accumulation of mast cells in the adventitia of unstable lesions in TN/E group. Collectively, our data point to an anti-inflammatory role for TN in vascular diseases. The overall goal of this proposal is to test 4 specific hypotheses (Aims). - Aim 1. A specific domain/segment of TN negatively regulates TNF-a induced VCAM-1 promoter activity. Aim 2. Chronic hyperlipidemia in TN/E mice up-regulates eotaxin promoting an accumulation of mast cells. Aim 3. TN deficiency promotes neointimal formation after vascular injury. Aim 4. TN deficiency per se is sufficient for neointimal formation.

描述（由申请人提供）：我们和其他人之前的研究已经使用细胞培养系统来建立 TN 的血管功能。现在，我们将这些观察扩展到体内，以检验以下假设：apo E-/-背景中TN的基因缺失可能会改变受损动脉和动脉粥样硬化病变中的新内膜增生。 TN/E 小鼠在接受高脂肪饮食一周后出现动脉粥样硬化病变。这种病变的发展比在 Apo E 小鼠中观察到的更快、更复杂。同时，仅在TN/E组中检测到VCAM-1表达。 FACS分析显示TN/E来源的内皮细胞中VCAM-1的表达水平明显高于apo E小鼠的VCAM-1表达水平。最后，发现当内皮细胞中的 TNF-α 诱导时，TN 会下调 VCAM-1 启动子活性。这些数据表明 TN 缺乏促进白细胞/内皮细胞相互作用。除了斑块的快速发展之外，TN/E小鼠的慢性高脂血症还导致不稳定斑块的形成。对两种小鼠基因型慢性高脂血症血浆的抗体阵列和 ELISA 分析表明，与 apo E 小鼠相比，TN/E 组中的 eotaxin（一种 CC 趋化因子）选择性上调 4 至 5 倍。此外，TN/E组不稳定病灶外膜内有肥大细胞聚集。总的来说，我们的数据表明 TN 在血管疾病中具有抗炎作用。该提案的总体目标是检验 4 个具体假设（Aims）。 - 目标 1. TN 的特定结构域/片段负向调节 TNF-a 诱导的 VCAM-1 启动子活性。目标 2. TN/E 小鼠的慢性高脂血症上调嗜酸细胞趋化因子，促进肥大细胞的积累。目标 3. TN 缺乏促进血管损伤后新内膜形成。目标 4. TN 缺乏本身足以形成新内膜。