Vascular calcification and atherosclerosis

血管钙化和动脉粥样硬化

• 批准号: 10542822
• 负责人: Olga V. Savinova
• 金额: $ 37.01万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542822
• 关键词: Ablation; Acceleration; Adverse effects; Alkaline Phosphatase; American; Aorta; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Attention; Benign; Biological Availability; Bone remodeling; Breast Microcalcification; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Cholesterol; Complement; Computer Models; Computer software; Coronary Arteriosclerosis; Coupled; Data; Development; Disease; Elasticity; Endothelial Cells; Endothelium; Familial Hypercholesterolemia; Future; General Population; Genetic; Genetic Recombination; Geometry; Goals; Heart Diseases; Histologic; Human; Hydroxyapatites; Hyperglycemia; Hypertension; Infusion procedures; Label; Left Ventricular Ejection Fraction; Lipids; Lipoproteins; Liquid substance; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macrophage; Measures; Mediating; Methods; Microscopic; Modeling; Monitor; Morbidity - disease rate; Motion; Mus; Nodule; Oral; Outcome; Pathogenesis; Patients; Phase; Phenotype; Physics; Plasma; Play; Preparation; Public Health; Resolution; Risk; Risk Factors; Role; Rupture; Structure; Surface; Testing; Texture; Therapeutic; Time; Tissues; United States; Vascular calcification; Virulence Factors; Visualization; Work; athero susceptible; bone; calcification; cardiovascular disorder risk; cardiovascular risk factor; care costs; cell type; experimental study; hemodynamics; human model; image guided; improved; improved outcome; in vivo; in vivo Model; microCT; modifiable risk; mortality; mouse model; mutant; novel; novel therapeutics; osteogenic; overexpression; particle; phosphatase inhibitor; preservation; response; risk stratification; shear stress; side effect; small molecule; targeted treatment; therapeutic development; therapeutic target; thrombotic complications; uptake

Project Summary/Abstract Cardiovascular disease (CVD) is the leading cause of death in the U.S., with the annual total cost of care estimated at $351 billion. Vascular calcification is a nontraditional CVD risk factor associated with a significant increase in morbidity and mortality in the general population. Unlike other established risk factors, it is not yet regarded as a modifiable factor. However, there is emerging evidence that it may drive the pathogenesis of atherosclerosis and play an important role in the regression of atherosclerotic plaques. Our data demonstrated that overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerated coronary atherosclerosis in hyperlipidemic mice, while the TNAP inhibitor SBI-425 reduced manifestations of coronary artery disease in this model. Subendothelial microcalcification was frequently observed in the internal elastic lamina in mice and in human arteries and was predicted by computational fluid structure interaction (FSI) modeling to redistribute wall shear stress on the endothelium. The idea that calcification can promote atherosclerosis was further supported by an observation of increased low density lipoprotein (LDL) uptake by endothelial cells cultured on surfaces textured with hydroxyapatite particles. More evidence from mouse models showed that TNAP activity in macrophages was sufficient to increase calcification during progression of atherosclerosis and interfere with plaque regression, leading to maladaptive dilation of the aortic root. We hypothesize that calcification is a modifiable factor in atherosclerosis and that inhibiting TNAP-mediated vascular calcification may have therapeutic value. The overarching goal of this project is to gain a better understanding of the role of calcification during atherosclerotic lesion initiation, progression, and resolution, and to determine whether calcification is an active pathogenic factor in atherosclerosis or a mere, likely benign, secondary response. The project will use computational and in vivo models to delineate hemodynamic mechanism by which subendothelial microcalcifications increases retention of LDL in the arterial wall. The effects of the conditional genetic ablation of TNAP in macrophages or an increase of TNAP activity in plasma will then be tested in a mouse model of familial hypercholesterolemia. Because regression of calcified plaques can lead to eccentric aortic root remodeling during lipid lowering, we will interrogate whether inhibition of TNAP with SBI-425 could suppress calcification and alleviate maladaptive remodeling of the aortic root in a mouse model during reversal of atherosclerosis. In testing TNAP inhibition for its therapeutic utility for atherosclerotic calcification, we will keep close attention on potential bone side effects by monitoring bone microarchitecture using micro-computed tomography. The results of this project will establish whether calcification is a modifiable risk factor in CVD and determine whether systemic TNAP inhibition or elimination of osteogenic TNAP-expressing macrophages is a viable therapeutic approach in atherosclerosis. The results of this study will help guide future development of novel therapeutics for this prevalent disease.

项目概要/摘要 心血管疾病 (CVD) 是美国的首要死亡原因，每年的总护理费用 估计为3510亿美元。血管钙化是一种非传统 CVD 危险因素，与显着相关 一般人群发病率和死亡率增加。与其他已确定的风险因素不同，目前还没有 视为可修改因素。然而，有新的证据表明它可能驱动以下疾病的发病机制： 动脉粥样硬化并在动脉粥样硬化斑块的消退中发挥重要作用。我们的数据证明 内皮细胞中组织非特异性碱性磷酸酶（TNAP）的过度表达加速 高脂血症小鼠的冠状动脉粥样硬化，而 TNAP 抑制剂 SBI-425 则减少了冠状动脉粥样硬化的表现 该模型中的冠状动脉疾病。内皮下微钙化经常在内部观察到 小鼠和人类动脉中的弹性层，并通过计算流体结构相互作用进行预测 (FSI) 建模以重新分配内皮上的壁剪切应力。钙化可以促进的想法 观察到低密度脂蛋白（LDL）摄取增加进一步支持动脉粥样硬化 在羟基磷灰石颗粒纹理的表面上培养内皮细胞。来自小鼠的更多证据 模型表明巨噬细胞中的 TNAP 活性足以在进展过程中增加钙化 动脉粥样硬化并干扰斑块消退，导致主动脉根部适应不良扩张。 我们假设钙化是动脉粥样硬化的一个可改变因素，并且抑制 TNAP 介导的钙化 血管钙化可能有治疗价值。该项目的总体目标是获得更好的 了解钙化在动脉粥样硬化病变发生、进展和消退过程中的作用， 并确定钙化是否是动脉粥样硬化的活性致病因素，或者仅仅是一种可能是良性的， 二次响应。该项目将使用计算和体内模型来描述血流动力学 内皮下微钙化增加动脉壁中 LDL 滞留的机制。这 巨噬细胞中 TNAP 条件性基因消除或血浆中 TNAP 活性增加的影响 然后将在家族性高胆固醇血症小鼠模型中进行测试。因为钙化斑块消退 降脂过程中会导致主动脉根部偏心重塑，我们将探讨是否抑制TNAP 与 SBI-425 一起使用可以抑制小鼠主动脉根部的钙化并减轻适应不良的重塑 逆转动脉粥样硬化过程中的模型。测试 TNAP 抑制对动脉粥样硬化的治疗作用 钙化，我们将通过监测骨微结构密切关注潜在的骨骼副作用 使用微型计算机断层扫描。该项目的结果将确定钙化是否是一种 CVD 中可改变的危险因素，并确定是否全身性 TNAP 抑制或消除 表达成骨 TNAP 的巨噬细胞是动脉粥样硬化的一种可行的治疗方法。这 这项研究的结果将有助于指导未来针对这种流行疾病的新疗法的开发。