Macrophage Akt and IKKalpha signaling in apoptosis and atherosclerosis

细胞凋亡和动脉粥样硬化中的巨噬细胞 Akt 和 IKKalpha 信号传导

• 批准号: 8284402
• 负责人: MACRAE F LINTON
• 金额: $ 46.14万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284402
• 关键词: Adipocytes; Antioxidants; Apoptosis; Apoptotic; Arterial Fatty Streak; Arteries; Atherosclerosis; Cardiovascular system; Cause of Death; Cell Count; Cell Death; Cells; Cellularity; Chemicals; Coagulation Process; Data; Development; Dinoprostone; Disease; EP4 receptor; Event; Foam Cells; Genes; Genetic; Goals; Hematopoietic; In Vitro; Inflammatory; Laboratories; Lesion; Lesion by Morphology; Mediating; Molecular; Mus; Myocardial Infarction; Necrosis; Nuclear; Pathway interactions; Phenotype; Phosphatidylinositols; Phosphoinositide Pathway; Phosphotransferases; Play; Prevention; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Relative (related person); Reporting; Role; Rupture; Secondary to; Senile Plaques; Signal Pathway; Signal Transduction; Signaling Protein; Staging; Stimulus; Stress; Stroke; artery occlusion; atherogenesis; cell type; defined contribution; fatty acid-binding proteins; human FRAP1 protein; human WFDC2 protein; in vivo; macrophage; member; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Atherosclerosis is a progressive inflammatory disease and the underlying cause of heart attack and stroke. Macrophages play a crucial role in the formation and progression of atherosclerotic lesions. Macrophage apoptosis occurs throughout all stages of atherosclerosis with a differential impact on lesion morphology in early versus late atherosclerosis. Loss of macrophages in early lesions is thought to reduce lesion size, whereas cell death in advanced lesions contributes to the necrotic core and plaque destabilization. Studies by Tabas and coworkers have demonstrated that defective phagocytic clearance results in apoptotic cell accumulation in atherosclerotic plaques. Here we propose that the intrinsic ability of macrophages to resist pro- apoptotic stimuli may be another important determinant of macrophage survival and apoptotic cell numbers in atherosclerotic lesions. There are two major pro-survival pathways, PI3K/Akt and NF-kB, and both are constitutively active in macrophages and macrophage-derived foam cells of atherosclerotic lesions. Recent studies in our laboratory have shown that genetic deficiency of the prostaglandin E2 receptor, EP4, in hematopoietic cells promotes macrophage apoptosis in atherosclerotic lesions by modulating the PI3K/Akt and NF-kB signaling pathways. Two Akt isoforms are expressed in macrophages, Akt1 and Akt2, yet their relative contributions to macrophage apoptosis and atherogenesis have not been determined. Interestingly, Akt has been reported to mediate signaling through IKKa that may activate the NF-kB pathways with its anti-apoptotic activity. We hypothesize that cross-talk between the Akt and NF-kB signaling pathways is a critical determinant of macrophage survival and atherogenesis. In this proposal we intend to define the contribution of distinct members of the Akt NF-kB signaling pathways, including Akt1, Akt2, and IKKa, to macrophage survival and atherosclerotic lesion formation. We hypothesize that both Akt-1 and Akt-2 contribute to macrophage survival but that deficiency of both isoforms will promote macrophage apoptosis to a greater extent than deficiency of either isoform alone. The goal of Specific Aim 1 is to examine the impact of hematopoietic cell deficiency of Akt1, Akt2, or both on macrophage survival and atherogenesis in LDLR-/- mice in vivo. The goal of Specific Aim 2 is to define the impact of macrophage deficiency of Akt1 and/or Akt2 on apoptosis and the Akt and NF- :B signaling pathways in vitro. Akt and IKKa are necessary for TORC1 formation in signal transduction. Therefore, we will examine the hypothesis that macrophage deficiency of Akt1 and/or Akt2 will suppress mTOR activity. In Specific Aim 3, we will examine the hypothesis that IKKa deficiency in hematopoietic cells will reduce macrophage survival and impact atherogenesis through alterations in the Akt and NF-:B signaling pathways. A better understanding of the molecular mechanisms of macrophage survival may provide new targets for the prevention of atherosclerosis and cardiovascular events. PUBLIC HEALTH RELEVANCE: As the underlying cause of heart attack and stroke, atherosclerosis (plaque formation in arteries) is the most common cause of death and suffering in the industrialized world. Macrophage apoptosis (programmed cell death) has been implicated in the development of atherosclerotic lesions and plaque rupture, which results in clot formation and arterial occlusion and heart attack. The goal of these studies is to define the roles of two key signaling proteins (Akt and IKKalpha) in macrophage survival and atherosclerosis, which will help define new targets for the prevention and treatment of atherosclerosis.

描述（由申请人提供）：动脉粥样硬化是一种进行性炎症性疾病，是心脏病发作和中风的根本原因。巨噬细胞在动脉粥样硬化病变的形成和发展中起着至关重要的作用。巨噬细胞凋亡发生在动脉粥样硬化的所有阶段，对早期和晚期动脉粥样硬化病变形态的影响不同。早期病变中巨噬细胞的损失被认为会减小病变大小，而晚期病变中的细胞死亡会导致坏死核心和斑块不稳定。塔巴斯及其同事的研究表明，吞噬细胞清除缺陷导致动脉粥样硬化斑块中凋亡细胞积聚。在此，我们提出巨噬细胞抵抗促凋亡刺激的内在能力可能是动脉粥样硬化病变中巨噬细胞存活和凋亡细胞数量的另一个重要决定因素。有两种主要的促存活途径，PI 3 K/Akt和NF-kB，并且两者在动脉粥样硬化病变的巨噬细胞和巨噬细胞衍生的泡沫细胞中组成性地活跃。我们实验室最近的研究表明，造血细胞中前列腺素E2受体EP 4的遗传缺陷通过调节PI 3 K/Akt和NF-kB信号通路促进动脉粥样硬化病变中的巨噬细胞凋亡。两种Akt亚型Akt 1和Akt 2在巨噬细胞中表达，但它们对巨噬细胞凋亡和动脉粥样硬化形成的相对作用尚未确定。有趣的是，Akt已经被报道通过IKKa介导信号传导，IKKa可以通过其抗凋亡活性激活NF-kB途径。我们假设Akt和NF-kB信号通路之间的相互作用是巨噬细胞存活和动脉粥样硬化形成的关键决定因素。在这个提议中，我们打算定义Akt NF-κ B信号通路的不同成员，包括Akt 1，Akt 2和IKKa，对巨噬细胞存活和动脉粥样硬化病变形成的贡献。我们假设Akt-1和Akt-2都有助于巨噬细胞的存活，但这两种亚型的缺乏将促进巨噬细胞凋亡到更大的程度比任何一种亚型单独缺乏。特定目的1的目的是检查Akt 1、Akt 2或两者的造血细胞缺乏对LDLR-/-小鼠体内巨噬细胞存活和动脉粥样硬化形成的影响。特定目标2的目标是确定Akt 1和/或Akt 2的巨噬细胞缺乏对细胞凋亡以及Akt和NF-：B信号通路的体外影响。Akt和IKKa是TORC 1形成所必需的信号转导途径。因此，我们将检验Akt 1和/或Akt 2的巨噬细胞缺陷将抑制mTOR活性的假设。在具体目标3中，我们将检验造血细胞中IKKa缺陷将通过Akt和NF-：B信号通路的改变减少巨噬细胞存活并影响动脉粥样硬化形成的假设。更好地了解巨噬细胞存活的分子机制可能为预防动脉粥样硬化和心血管事件提供新的靶点。 公共卫生关系：作为心脏病发作和中风的根本原因，动脉粥样硬化（动脉中的斑块形成）是工业化世界中死亡和痛苦的最常见原因。巨噬细胞凋亡（程序性细胞死亡）与动脉粥样硬化病变和斑块破裂的发展有关，导致凝块形成和动脉闭塞以及心脏病发作。这些研究的目的是确定两种关键信号蛋白（Akt和IKK α）在巨噬细胞存活和动脉粥样硬化中的作用，这将有助于确定预防和治疗动脉粥样硬化的新靶点。