12/15-LIPOXYGENASE, INSULIN-LIKE GROWTH FACTOR-1 AND ATHEROSCLEROSIS

12/15-脂加氧酶、胰岛素样生长因子-1 和动脉粥样硬化

• 批准号: 8965578
• 负责人: Sergiy Sukhanov
• 金额: $ 18.44万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965578
• 关键词: 12; 15; LIPOXYGENASE; INSULIN; LIKE

DESCRIPTION (provided by applicant): Atherosclerosis is the principal underlying cause of most cardiovascular disease-related deaths and there is a great need to develop innovative therapies targeting overall disease burden and to decrease acute vascular events related to plaque instability. Atherosclerosis is an inflammatory disease in which macrophages and macrophage-derived foam cells play a pre-dominant role. Recent findings indicate that insulin-like growth factor-1 (IGF-1) reduces atherosclerotic burden and increases features of plaque stability in Apoe-/- mice and these effects correlate with reduced plaque macrophages and lipid levels and decreased foam cells. However, mechanisms whereby IGF-1 exerts vasculoprotective effects are unclear. The goal of this exploratory project is to determine mechanism whereby IGF-1 alters lipid uptake in macrophages and reduces atherosclerotic burden. My preliminary data demonstrate that IGF-1 downregulates 12/15-lipoxygenase (12/15- LOX) expression in Apoe-/- mice and in cultured macrophages. The latter effect correlates with decreased cell- mediated lipid oxidation and reduced lipid uptake. 12/15-LOX mediates the transformation of low density lipoprotein into its oxidized form and via this mechanism 12/15-LOX enhances macrophage lipid uptake and promotes formation of foam cells. I will focus this short-term R21 exploratory proposal on studying the transcriptional mechanism of IGF-1-induced 12/15-LOX regulation in macrophages and I will also determine the importance of IGF-1 downregulation of 12/15-LOX and the specific role of macrophage 12/15-LOX for its anti-atherosclerotic effect. The central hypothesis is that IGF-1 downregulates 12/15-LOX in macrophages via reduced expression and/or activity of STAT-6 transcription factor. This suppression of macrophage 12/15-LOX is critical for IGF-1-induced reduction in atherosclerotic plaque burden. Two specific aims have been designed: Specific Aim 1. To study the transcriptional mechanism mediating IGF-1-induced downregulation of 12/15-LOX in macrophages. Specific Aim 2. To study whether 12/15-LOX downregulation mediates IGF-1-induced reduction in atherosclerotic plaque burden. Expected outcome: I anticipate that IGF-1-induced suppression of STAT-6 will downregulate macrophage 12/15-LOX and this mechanism will mediate the reduced macrophage lipid uptake. I expect to demonstrate that macrophage-specific 12/15-LOX is the critical mediator of IGF-1-induced anti-atherosclerotic effects in Apoe-/- mice. Overall, these findings will establish the role of 12/15-LOX as a key component of IGF-1-induced suppression of macrophage lipid uptake in vitro and IGF-1-induced atheroprotection in Apoe-/- mice. The anticipated results of this R21 will serve as essential experimental support for the preparation of a future full- scale (R01) proposal focusing on studying cell-targeted effects of IGF-1. In addition, I anticipate that identification of molecular mechanisms regulating 12/15-LOX expression will offer new targets for therapeutic intervention.

描述（由申请人提供）：动脉粥样硬化是大多数心血管疾病相关死亡的主要潜在原因，因此非常需要开发针对总体疾病负担的创新疗法，并减少与斑块不稳定性相关的急性血管事件。动脉粥样硬化是一种炎症性疾病，其中巨噬细胞和巨噬细胞衍生的泡沫细胞发挥主导作用。最近的研究结果表明，胰岛素样生长因子-1（IGF-1）可降低Apoe-/-小鼠的动脉粥样硬化负荷并增加斑块稳定性，这些作用与斑块巨噬细胞和脂质水平降低以及泡沫细胞减少相关。然而，IGF-1发挥血管保护作用的机制尚不清楚。该探索性项目的目标是确定IGF-1改变巨噬细胞中脂质摄取并降低动脉粥样硬化负荷的机制。我的初步数据表明，IGF-1下调12/15-脂氧合酶（12/15- LOX）在Apoe-/-小鼠和培养的巨噬细胞的表达。后一种效应与细胞介导的脂质氧化减少和脂质摄取减少相关。12/15-LOX介导低密度脂蛋白向其氧化形式的转化，并且通过该机制12/15-LOX增强巨噬细胞脂质摄取并促进泡沫细胞的形成。我将把这个短期的R21探索性建议集中在研究IGF-1诱导的巨噬细胞12/15-LOX调节的转录机制上，我还将确定IGF-1下调12/15-LOX的重要性以及巨噬细胞12/15-LOX在其抗动脉粥样硬化作用中的特定作用。中心假设是IGF-1通过降低STAT-6转录因子的表达和/或活性下调巨噬细胞中的12/15-LOX。这种对巨噬细胞12/15-LOX的抑制对于IGF-1诱导的动脉粥样硬化斑块负荷的减少至关重要。制定了两个具体目标：具体目标1。研究IGF-1诱导巨噬细胞12/15-LOX下调的转录机制。具体目标2。研究12/15-LOX下调是否介导IGF-1诱导的动脉粥样硬化斑块负荷减少。预期成果：我预计IGF-1诱导的STAT-6抑制将下调巨噬细胞12/15-LOX，这种机制将介导巨噬细胞脂质摄取的减少。我希望证明巨噬细胞特异性12/15-LOX是IGF-1诱导的Apoe-/-小鼠抗动脉粥样硬化作用的关键介质。总之，这些发现将确立12/15-LOX作为体外IGF-1诱导的巨噬细胞脂质摄取抑制和IGF-1诱导的Apoe-/-小鼠动脉粥样硬化保护的关键组分的作用。该R21的预期结果将作为制备未来全规模（R 01）提案的必要实验支持，该提案侧重于研究IGF-1的细胞靶向作用。此外，我预计，鉴定调节12/15-LOX表达的分子机制将为治疗干预提供新的靶点。