15-LOX-15(S)-HETE axis and angiogenesis

15-LOX-15(S)-HETE 轴和血管生成

基本信息

批准号：
7589829
负责人：
GADIPARTHI N RAO
金额：
$ 36.5万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7589829
关键词：
13-hydroxyoctadecadienoic acid Abbreviations Angiogenesis Inducing Agents Antibodies Aorta Apolipoprotein E Applications Grants Arachidonate 12-Lipoxygenase Arachidonate 15-Lipoxygenase Arachidonic Acids Arterial Fatty Streak Atherosclerosis Biological Assay Blood Vessels Cardiovascular Diseases Cells Cornea Culture Media Cytochrome P450 Dermal Development Diet Dominant-Negative Mutation Drug or chemical Tissue Distribution EMSA Eicosanoids Electrophoretic Mobility Shift Assay Endothelial Cells Epithelial Cells Event Fatty acid glycerol esters Fibroblast Growth Factor Fibroblast Growth Factor 2 Funding Gelatinase A Genes Goals Growth Hand Human Hydroxyeicosatetraenoic Acids Indium Inflammatory Knockout Mice Laboratories Lesion Linoleic Acids Lipids Low Density Lipoprotein oxidation Lung Matrix Metalloproteinases Mediating Mixed Function Oxygenases Molecular Mus Nuclear Oxidoreductase P-2 PECAM1 gene Pathogenesis Play Polymerase Chain Reaction Production Promoter Regions Prostate RNA Interference Regulation Regulatory Element Reporting Research Project Grants Research Proposals Reticulocytes Reverse Transcription Role Run-On Assays Series Signal Transduction Simvastatin Site Skin Small Interfering RNA Smooth Muscle Myocytes Testing Therapeutic Agents Time Transgenic Mice Tube Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Western Blotting Work angiogenesis cell motility cell type chromatin immunoprecipitation feeding glutaryl coA inhibitor/antagonist macrophage matrigel mevalonate migration monocyte novel overexpression promoter public health relevance research study response restenosis

项目摘要

DESCRIPTION (provided by applicant): The presence of two 15-lipoxygenases (15-LOXs), namely, 15-LOX1 and 15-LOX2, has been reported in humans. 15-LOX1 while preferentially metabolizes linoleic acid (LA) to 13(S)-hydroxyoctadecadienoic acid (13(S)-HODE) also converts arachidonic acid (AA) to 15-hydroxyeicosatetraenoic acid (15(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). On the other hand, 15-LOX2 specifically metabolizes AA to 15(S)-HETE. In regard to their tissue distribution, 15-LOX1 has been shown to be present in a wide variety of cell types including reticulocytes, macrophages and monocytes, whereas the expression of 15-LOX2 appears to be restricted to epithelial cell types in cornea, lung, prostate and skin. Although the presence of 15-LOX2 in the vessel wall has not been reported yet, vascular smooth muscle cells (VSMC) and endothelial cells (EC) express 15-LOX1 (also known as 12/15-LOX in murines) and when these cells are exposed to AA, they produce both 15(S)-HETE and 12(S)-HETE. Although, the involvement of 12(S)-HETE in vascular diseases has been fairly studied, relatively nothing is known about the role of 15(S)-HETE. In this aspect, the work in our laboratory pointed out that 15(S)-HETE is a potent stimulator of angiogenesis. Since angiogenesis plays a crucial role in vascular diseases, it is essential to investigate whether 15-LOX-15(S)-HETE axis, via inducing angiogenesis, influences vascular diseases. Towards achieving this goal, we propose to study the following five specific aims. Specific Aim 1: To determine the role of Egr-1 in 15(S)-HETE-induced human dermal micro vascular endothelial cell (HDMVEC) migration and tube formation and aortic ring and Matrigel plug angiogenesis. Specific Aim 2: 15(S)-HETE-induced HDMVEC migration and tube formation and aortic ring and Matrigel plug angiogenesis require Egr-1-mediated induction of expression of fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF). Specific Aim 3: 15(S)-HETE-induced HDMVEC migration and tube formation and aortic ring and Matrigel plug angiogenesis require 3-hydroxy-3-methyl glutaryl coenzyme-A reductase (HMGCR) activity. Specific Aim 4: 15(S)-HETE-induced HDMVEC migration and tube formation and aortic ring and Matrigel plug angiogenesis require HMGCR-dependent expression and release of matrix metalloproteinases (MMP)-2 and -9. Specific Aim 5: Inhibition of 12/15-LOX reduces intraplaque angiogenesis and atherosclerotic lesions. The results of the experiments proposed in the above-listed five specific aims will provide novel information in terms of the role of 15-LOX-15(S)-HETE axis in vascular diseases and the potential new mechanisms by which this lipid molecule exerts such vascular wall remodeling.

描述（由申请人提供）：在人类中，已经报道了两个15-脂氧酶（15-氧酶），即15-LOX1和15-LOX2。 15-LOX1 while preferentially metabolizes linoleic acid (LA) to 13(S)-hydroxyoctadecadienoic acid (13(S)-HODE) also converts arachidonic acid (AA) to 15-hydroxyeicosatetraenoic acid (15(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid （12（s）-HETE）。另一方面，15-LOX2专门将AA代谢为15（s）-HETE。关于其组织分布，已证明15-LOX1存在于多种细胞类型中，包括网状细胞，巨噬细胞和单核细胞，而15-LOX2的表达似乎仅限于角膜，肺，前列腺和皮肤的上皮细胞类型。尽管尚未报道血管壁中15-LOX2的存在，但血管平滑肌细胞（VSMC）和内皮细胞（EC）表达15-LOX1（也称为鼠鼠中的12/15-lox），当这些细胞暴露于AA时，它们会产生15（s）-HETE和12（S）-HETE和12（S）-HETE。虽然，已经对12（s） - hete参与血管疾病的参与得到了公平研究，但对15（s）hete的作用一无所知。在这方面，我们实验室中的工作指出，15（s） - hete是血管生成的有效刺激剂。由于血管生成在血管疾病中起着至关重要的作用，因此必须通过诱导血管生成来研究15-lox-15（S）旋转轴是否会影响血管疾病。为了实现这一目标，我们建议研究以下五个特定目标。具体目的1：确定Egr-1在15（s）诱导的人类皮肤微血管内皮细胞（HDMVEC）迁移和管形成以及主动脉环和基质塞血管生成的作用。具体目标2：15（S） - 诱导的HDMVEC迁移和管形成以及主动脉环和基质塞血管生成需要EGR-1介导的成纤维细胞生长因子（FGF）-2和血管内皮生长因子（VEGFF）的表达诱导。特定的目标3：15（S）诱导的HDMVEC迁移和管形成以及主动脉环和矩阵塞血管生成需要3-羟基-3-甲基谷物凝胶核-A还原酶（HMGCR）活性。特定的目标4：15（S） - 诱导的HDMVEC迁移和管形成以及主动脉环和基质塞血管生成需要HMGCR依赖性的表达，并释放基质金属蛋白酶（MMP）-2和-9。具体目的5：抑制12/15-lox可减少内部血管生成和动脉粥样硬化病变。在上述五个特定目标中提出的实验结果将提供新的信息，以15-LOX-15（S） - 旋转轴在血管疾病中的作用以及该脂质分子施加这种血管壁重塑的潜在新机制。