AIBP and Endothelial Function

AIBP 和内皮功能

• 批准号: 8885205
• 负责人: Yury Miller
• 金额: $ 51.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885205
• 关键词: Address; Adhesions; Animal Model; Aorta; Apolipoprotein A-I; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; Binding Proteins; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell membrane; Cell model; Cell physiology; Cells; Cholesterol; Consensus; Development; Diet; Disease; Dyslipidemias; Endothelial Cells; Event; Foam Cells; Future; High Density Lipoproteins; Human; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Knockout Mice; Lead; Leukocytes; Lipids; Lipoproteins; Low-Density Lipoproteins; Measures; Mediating; Membrane Lipids; Membrane Microdomains; Modeling; Modification; Morbidity - disease rate; Mus; Myocardial Infarction; Nature; Pathology; Patients; Peptides; Peripheral arterial disease; Plasma; Play; Population; Prevention; Process; Property; Protein Deficiency; Proteins; Publishing; Raisins; Receptor Signaling; Recombinants; Recruitment Activity; Role; Sampling; Signal Pathway; Smooth Muscle Myocytes; Stroke; Surface; Testing; Therapeutic; Therapeutic Effect; Tissues; United States; Vascular Permeabilities; Zebrafish; atheroprotective; base; cardiovascular disorder risk; cardiovascular disorder therapy; chemokine; cytokine; endothelial dysfunction; feeding; improved; in vivo; macrophage; monocyte; mortality; mouse model; novel; oxidized low density lipoprotein; paracrine; prevent; protein expression; public health relevance; research study; transcytosis; vascular inflammation

 DESCRIPTION (provided by applicant): Inflammation and lipid accumulation in the vascular wall constitute critical events in initiation and progression of cardiovascular disease, manifested in myocardial infarction and stroke in more than a half of the US population. Activated endothelial cells (EC) secrete chemokines and express adhesion molecules to recruit leukocytes to the vascular wall. Oxidized LDL and dysfunctional HDL play a major role in EC-mediated inflammation, whereas functional HDL preserves the EC integrity and prevents inflammatory responses. One of the major mechanisms by which HDL exerts its protective function is cholesterol efflux from the plasma membrane of EC. We discovered that apoA-I binding protein (AIBP) significantly improves HDL function by accelerating cholesterol efflux from EC. AIBP is a secreted protein and its effect on EC is paracrine and non-cell autonomous. These findings open the possibility of using AIBP or AIBP-derived peptides as a therapy to improve the cholesterol efflux function of HDL and thereby prevent and/or reverse vascular pathology. Here we propose to test the hypothesis that AIBP reduces EC inflammatory responses via modulation of cholesterol efflux and lipid rafts. We will test this hypothesis in cellular models as well as in aorta explants, by measuring expression of cytokines and adhesion molecules, probing relevant signaling pathways, detecting ROS, apoptosis and autophagy, and assessing LDL transcytosis and monocyte adhesion. Further, we will determine effects of systemic and tissue-specific AIBP deficiency on endothelial function. We have developed Aibp LoxP and Aibp knockout mice, which are viable and fertile. AIBP expression has been detected in macrophages and vascular smooth muscle cells (VSMC) of mouse atherosclerotic lesions. Thus, we propose that AIBP secreted by macrophages and/or VSMC protects aortic EC and that deletion of Aibp in these cells will lead to exacerbated EC inflammatory responses and increased atherosclerosis burden. We also hypothesize that, conversely, raising AIBP levels will improve endothelial function and reduce inflammation. The hypothesis will be tested in vivo with mouse and zebrafish animal models and ex vivo with human plasma samples obtained from patients with dyslipidemia and/or cardiovascular disease (CVD). In a hypercholesterolemic zebrafish model, we expect that conditional expression of Aibp will reduce vascular lipid accumulation, foam cell formation, membrane lipid order in EC, and vascular permeability. In a hypercholesterolemic mouse model, we expect that infusion of recombinant AIBP, alone or in combination with apoA-I, will reduce EC inflammation and atherosclerosis. In addition, human plasma and HDL isolated from CVD patients will be supplemented with recombinant AIBP and tested for their effect on monocyte adhesion to EC. We expect that AIBP will improve protective properties of dysfunctional HDL. Results of these experiments, if positive, will facilitate future development of AIBP-based therapeutic applications.

 描述（申请人提供）：血管壁炎症和脂质积聚构成心血管疾病发生和进展的关键事件，表现为 在超过一半的美国人口中发生心肌梗死和中风。活化的内皮细胞（EC）分泌趋化因子并表达粘附分子以将白细胞募集到血管壁。氧化的LDL和功能失调的HDL在EC介导的炎症中起主要作用，而功能性HDL保持EC完整性并防止炎症反应。高密度脂蛋白发挥其保护作用的主要机制之一是胆固醇从EC质膜流出。我们发现apoA-I结合蛋白（AIBP）通过加速胆固醇从EC流出而显著改善HDL功能。AIBP是一种分泌性蛋白，其对EC的作用是旁分泌的，非细胞自主的。这些发现开启了使用AIBP或AIBP衍生肽作为治疗以改善HDL的胆固醇流出功能并由此预防和/或逆转血管病理的可能性。在这里，我们建议测试的假设，AIBP通过调节胆固醇流出和脂筏减少EC炎症反应。我们将在细胞模型以及主动脉外植体中测试这一假设，通过测量细胞因子和粘附分子的表达，探测相关信号通路，检测ROS，凋亡和自噬，并评估LDL转胞吞作用和单核细胞粘附。此外，我们将确定系统性和组织特异性AIBP缺乏对内皮功能的影响。我们已经开发了Aibp LoxP和Aibp敲除小鼠，它们是可行的和可繁殖的。在小鼠动脉粥样硬化病变的巨噬细胞和血管平滑肌细胞（VSMC）中检测到AIBP表达。因此，我们提出，由巨噬细胞和/或VSMC分泌的AIBP保护主动脉EC，并且这些细胞中AIBP的缺失将导致EC炎症反应加剧和动脉粥样硬化负担增加。我们还假设，相反，提高AIBP水平将改善内皮功能并减少炎症。将在小鼠和斑马鱼动物模型体内以及从血脂异常和/或心血管疾病（CVD）患者中获得的人血浆样本离体检验该假设。在高胆固醇血症斑马鱼模型中，我们预期Aibp的条件性表达将减少血管脂质积聚、泡沫细胞形成、EC中的膜脂质顺序和血管通透性。在高胆固醇血症小鼠模型中，我们预期单独或与apoA-I组合输注重组AIBP将减少EC炎症和动脉粥样硬化。此外，将用重组AIBP补充从CVD患者分离的人血浆和HDL，并测试其对单核细胞粘附至EC的影响。我们希望AIBP能改善功能失调的HDL的保护特性。这些实验的结果，如果是积极的，将促进未来的发展AIBP为基础的治疗应用。