Oxidized-LDL, LOX-1 and angiogenesis

氧化 LDL、LOX-1 和血管生成

• 批准号: 7791637
• 负责人: JAWAHAR L MEHTA
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791637
• 关键词: Address; Antibodies; Apoptosis; Area; Arterial Fatty Streak; Arteries; Arts; Atherosclerosis; Binding; Biological Assay; Blood Vessels; Blood capillaries; CD36 gene; Cell Proliferation; Cells; Cessation of life; Cholesterol; Chronic; Coronary artery; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Dyslipidemias; Embryonic Development; Endothelial Cells; Event; Extracellular Matrix Degradation; Foam Cells; Functional disorder; Generations; Genes; Growth; Growth Factor; Human; Hydrogen Peroxide; Hypertension; Inflammatory; Ischemia; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; LOX gene; Lead; Lectin; Lesion; Low-Density Lipoproteins; Malignant Neoplasms; Mediating; Microarray Analysis; Modeling; Molecular; Molecular Biology; Mus; Myocardial Infarction; Necrosis; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Pathologic; Physiological; Physiological Processes; Play; Process; Reactive Oxygen Species; Research; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Smoking; Superoxides; Testing; Tissues; Training; Tube; Up-Regulation; Vascular Endothelial Growth Factors; Work; Wound Healing; angiogenesis; atherogenesis; base; capillary; cardiovascular risk factor; cell injury; cell motility; design; experience; inhibitor/antagonist; low density lipoprotein inhibitor; macrophage; matrigel; member; migration; mouse model; neovasculature; novel; oxidized LDL receptors; oxidized low density lipoprotein; preconditioning; public health relevance; receptor; research study; response; scavenger receptor; uptake

DESCRIPTION (provided by applicant): Summary: Angiogenesis, defined as formation of new blood vessels, is a physiological process necessary for embryonic development and wound repair. Angiogenesis is also an important component of various pathologic events such as tissue ischemia, cancer, diabetic retinopathy, and chronic inflammatory states including atherosclerosis. Among the key events leading to angiogenesis is generation of reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide which play a key role in physiological and pathophysiological states. LOX-1, a lectin-like ox-LDL receptor, is responsible for binding and uptake of ox-LDL in endothelial cells. It has been well documented that the activation of LOX-1 itself can stimulate the formation of ROS and initiate a cascade of redox-sensitive signaling events. We postulate that oxidized LDL (ox-LDL) at low concentrations activates LOX-1 in endothelial cells, induces low levels of ROS release and initiates the angiogenic response. Our specific aims in this proposal are: Aim # 1: To study the effect of oxidized LDL (ox-LDL) on angiogenesis- These studies will be done in human coronary artery endothelial cells, in an aortic ring model of angiogenesis, as well as in wild-type and LOX-1 knock out (KO) mice. Aim # 2: To define the mechanisms of ox-LDL-induced angiogenic response- These studies will involve a number of specific inhibitors, LOX-1 antibody, siRNA against LOX-1, and upregulation of LOX-1, and will involve state-of-art molecular biology approaches. Further, to define the mechanism of the effects of ox-LDL, microarray technology will be utilized to identify genes that are up-regulated and down-regulated during angiogenesis. The strengths of the proposal are: 1. The PI has strong background on angiogenesis and LOX-1 research. 2. The PI has LOX-1 KO mice in his possession. 3. Availability of well trained molecular biologist well-versed in most aspects of the research. 4. One of the PI's team members has extensive experience in microarray technology. Significance: Understanding of the basis of formation of neovasculature may provide novel information on the basis of atherogenesis, especially in the development of unstable lesions. Information gained from this study may also have relevance in the development of cancers which are dependent of neovasculature for their growth. PUBLIC HEALTH RELEVANCE: Narrative Hardening of the arteries (also known as atherosclerosis) is the cause of heart attacks. As the area covered with atherosclerosis grows, there is formation of small new blood vessels; a process called "angiogenesis". Angiogenesis is caused in part by oxygen-derived molecules called reactive oxygen species (ROS). Our work has shown that ROS stimulate a receptor for oxidized cholesterol called LOX- 1. The proposed experiments are designed to test the concept that oxidized cholesterol at low concentration activates LOX-1, induces low levels of ROS release and initiates angiogenesis. In contrast, high concentration of ROS causes much LOX-1 expression and cell injury. To confirm the role of LOX-1 in angiogenesis, we will use specialized mice that lack the LOX-1. In the second set of experiments, we will study the underlying mechanisms of angiogenesis by examining changes in genes. Information from this study may be important in understanding the development of atherosclerosis and certain cancers that are dependent of angiogenesis.

描述（由申请人提供）： 摘要：血管生成，定义为新血管的形成，是胚胎发育和伤口修复所必需的生理过程。血管生成也是各种病理事件的重要组成部分，例如组织缺血，癌症，糖尿病性视网膜病和包括动脉粥样硬化在内的慢性炎症状态。导致血管生成的关键事件之一是产生活性氧（ROS），例如超氧化物阴离子和过氧化氢，它们在生理和病理生理状态中起关键作用。 LOX-1是一种凝集素样的OX-LDL受体，负责内皮细胞中OX-LDL的结合和摄取。已经有充分的文献证明，LOX-1本身的激活可以刺激ROS的形成并启动一系列氧化还原敏感的信号事件。我们假设在低浓度下氧化的LDL（OX-LDL）激活内皮细胞中的LOX-1，诱导ROS释放的低水平并启动血管生成反应。我们在该提案中的具体目的是：目标＃1：研究氧化的LDL（OX-LDL）对血管生成的影响 - 这些研究将在人类冠状动脉内皮细胞中进行，在主动脉复原的主动脉环模型中，以及在野生型和LOX-1敲除（KO）小鼠中。目的＃2：定义OX-LDL诱导的血管生成反应的机制 - 这些研究将涉及许多特定的抑制剂，LOX-1抗体，针对LOX-1的siRNA和LOX-1的上调，并将涉及态度的分子生物学方法。此外，为了定义OX-LDL效应的机制，将利用微阵列技术来识别在血管生成过程中上调和下调的基因。该提案的优势是：1。PI在血管生成和LOX-1研究方面具有强大的背景。 2。PI拥有Lox-1 KO老鼠。 3。训练有素的分子生物学家的可用性在研究的大多数方面都有良好的影响。 4。PI的团队成员之一在微阵列技术方面拥有丰富的经验。意义：了解新生血管形成基础的理解可能会基于动脉粥样硬化提供新的信息，尤其是在不稳定病变的发展中。从这项研究中获得的信息也可能与癌症的发展相关，这些癌症依赖于新生血管的生长。 公共卫生相关性： 动脉的叙事硬化（也称为动脉粥样硬化）是心脏病发作的原因。随着覆盖着动脉粥样硬化的区域的增长，形成了小的新血管。一个称为“血管生成”的过程。血管生成部分是由称为活性氧（ROS）的氧衍生分子引起的。我们的工作表明，ROS刺激一种称为LOX-1的氧化胆固醇的受体。提出的实验旨在测试以下低浓度氧化胆固醇激活LOX-1的概念，可诱导低水平的ROS释放并启动血管生成。相反，高浓度的ROS会导致许多LOX-1表达和细胞损伤。为了确认LOX-1在血管生成中的作用，我们将使用缺乏LOX-1的专门小鼠。在第二组实验中，我们将通过检查基因的变化来研究血管生成的潜在机制。这项研究的信息对于理解动脉粥样硬化的发展和某些依赖血管生成的癌症可能很重要。