Role of IgE in Atherosclerosis

IgE 在动脉粥样硬化中的作用

基本信息

批准号：
8448117
负责人：
GUO-PING SHI
金额：
$ 40.47万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448117
关键词：
Acute myocardial infarction Adoptive Transfer Affinity Allergic Reaction Angina Pectoris Antibodies Apolipoprotein E Apoptosis Apoptotic Area Arterial Fatty Streak Atherosclerosis Binding Blocking Antibodies Blood Platelets Blood Vessels Cell Culture Techniques Cell Death Cell physiology Cells Chest Complex Control Animal Coronary heart disease Data Dendritic Cells Deposition Diet Endothelial Cells Exposure to Foam Cells Functional disorder Funding Human Hyperlipidemia Hypersensitivity IgE IgE Receptors Immunoblot Analysis Immunology Immunoprecipitation In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interruption Knock-out Lesion Ligands Lipids Lipopolysaccharides Low Density Lipoprotein Receptor M cell Macrophage Activation Mediating Mitogen-Activated Protein Kinases Molecular Mus NHE1 Necrosis Parasites Pathogenesis Pathway interactions Patients Plant Roots Plasma Cells Process Production Resistance Role Serum Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Stimulus Surface TLR2 gene Testing Toll-like receptors Unstable angina Ursidae Family Vascular Diseases abdominal aorta alanylglycine allergic response aortic arch atherogenesis base cell type chemokine cytokine eosinophil ethylisopropylamiloride extracellular in vivo inhibitor/antagonist macrophage mast cell monocyte novel omalizumab oxidized low density lipoprotein particle receptor reconstitution research study response toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Immunoglobulin E (IgE) associates with allergic responses, but we found that its serum levels are enhanced in patients with acute myocardial infarction or unstable angina pectoris; they are nearly double those in patients with stable angina pectoris or without coronary heart disease. Both IgE and its high-affinity receptor Fc¿R1 were expressed highly in human atherosclerotic lesions, localized to areas rich in macrophages (M¿), and colocalized to lesion smooth-muscle cells (SMCs) and endothelial cells (ECs). Preliminary experiments showed that in the absence of Fc¿R1 ¿-subunit, atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice developed 75% fewer lipid depositions in the thoracic-abdominal aorta and had a >50% reduction in atherosclerotic lesion sizes in the aortic arch, compared with Apoe-/- control mice. In vitro cell culture studies demonstrated that IgE induced activation of M¿, SMC, and EC mitogen-activated protein kinase (MAPK) pathway, along with enhanced inflammatory molecule production and apoptosis. Surprisingly, IgE stimulated a complex formation between Fc¿R1 ¿-chain and Toll-like receptor 4 (TLR4). Both Fc¿R1 ¿-subunit and TLR4 are necessary for IgE-induced M¿ cytokine and chemokine expression and apoptosis. Furthermore, these activities of IgE on M¿ associate with activation of Na+-H+ exchanger NHE1, followed by extracellular pH reduction. These novel preliminary findings are consistent with prior observations that in human atherosclerotic lesions, apoptotic cells cluster around lipid-rich necrotic cores, where the pH values are significantly lower (pH 7.15¿0.01) than in other areas of the same lesions (pH 7.55¿0.32, P=0.0001). Therefore, we hypothesize that IgE contributes to atherosclerosis by regulating M¿, vascular SMC, and EC inflammation and apoptosis, and that these processes depend on Fc¿R1 and TLR4 interaction as well as on NHE1 activation. We propose two specific aims to test this hypothesis: 1). To examine the molecular mechanisms by which IgE stimulates M¿ and vascular SMC and EC inflammation and apoptosis. 2). To examine whether inhibition or deficiency of IgE or IgE receptor Fc¿R1 reduces atherosclerosis, and to test the importance of IgE-mediated M¿ activation in atherogenesis. We anticipate that the experiments proposed in both aims will establish an important and novel role of IgE in M¿ and vascular cell pathobiology, and a direct participation of IgE in atherogenesis.

描述（申请人提供）：免疫球蛋白E（IgE）与过敏反应有关，但我们发现其血清水平在急性心肌梗塞或不稳定型心绞痛患者中升高，几乎是稳定型心绞痛或非稳定型心绞痛患者的两倍。 IgE 及其高亲和力受体 Fc¿ R1 在人类动脉粥样硬化病变中高度表达，定位于富含巨噬细胞 (M¿) 的区域，并共定位于病变平滑肌细胞 (SMC) 和内皮细胞 (EC) 初步实验表明，在缺乏 Fc¿ R1 ??与 Apoe-/ 相比，易发生动脉粥样硬化的载脂蛋白 E 缺陷 (Apoe-/-) 小鼠的胸腹主动脉脂质沉积减少 75%，主动脉弓动脉粥样硬化病变大小减少 50% 以上- 对照小鼠的体外细胞培养研究表明 IgE 诱导 M¿ 、SMC 和 EC 丝裂原激活蛋白激酶 (MAPK) 途径，以及增强的炎症分子产生和细胞凋亡，令人惊讶的是，IgE 刺激了 Fc¿ 之间的复合物形成。 R1 ?? -链和 Toll 样受体 4 (TLR4) 均为 Fc¿ R1 ?? -亚基和 TLR4 对于 IgE 诱导的 M¿ 是必需的此外，IgE 对 M¿ 的这些活性。与 Na+-H+ 交换器 NHE1 的激活有关，随后细胞外 pH 值降低。这些新颖的初步发现与先前的观察结果一致，即在人类动脉粥样硬化病变中，凋亡细胞聚集在富含脂质的坏死核心周围，其中 pH 值明显较低。（pH 7.15¿0.01）高于相同病变的其他区域（pH 7.55¿0.32，P = 0.0001）。 IgE 通过调节 M¿ 导致动脉粥样硬化、血管 SMC 和 EC 炎症和细胞凋亡，并且这些过程依赖于 Fc¿ R1 和 TLR4 相互作用以及 NHE1 激活我们提出了两个具体目标来检验这一假设：1) 检查 IgE 刺激 M¿以及血管 SMC 和 EC 炎症和细胞凋亡 2) 检查 IgE 或 IgE 受体 Fc 是否受到抑制或缺乏。 R1 减少动脉粥样硬化，并测试 IgE 介导的 M¿我们预计两者中提出的实验将确定 IgE 在 M¿和血管细胞病理学，以及 IgE 直接参与动脉粥样硬化形成。