Vascular calcification and atherosclerosis

项目摘要/摘要 心血管疾病(CVD)是美国主要的死亡原因，每年的总医疗费用 估计为3510亿美元。血管钙化是一种非传统的心血管危险因素，与显著的 普通人群中发病率和死亡率的增加。与其他已确定的风险因素不同，它还不是 被认为是可改变的因素。然而，有新的证据表明，它可能推动了 并在动脉粥样硬化斑块消退中发挥重要作用。我们的数据显示 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减少了 在这个模型中有冠状动脉疾病。内皮下微钙化常见于内 通过计算流体结构相互作用预测小鼠和人动脉中的弹性板层 (FSI)建模以在内皮上重分布壁切应力。钙化可以促进 观察到低密度脂蛋白(LDL)摄取增加，进一步支持了动脉粥样硬化 在含有羟基磷灰石颗粒的表面上培养内皮细胞。来自MICE的更多证据 模型显示巨噬细胞中的tnap活性足以增加进展过程中的钙化。 可能导致动脉粥样硬化，干扰斑块消退，导致主动脉根部不适应性扩张。 我们假设钙化是动脉粥样硬化中的一个可改变的因素，并且抑制TNAP介导的 血管钙化可能具有治疗价值。这个项目的首要目标是获得更好的 了解钙化在动脉粥样硬化病变发生、发展和消退过程中的作用 并确定钙化是动脉粥样硬化中的一个活跃的致病因素，还是仅仅是一个可能的良性因素， 二次反应。该项目将使用计算和活体模型来描绘血液动力学 内皮下微钙化增加低密度脂蛋白在动脉壁中滞留的机制。这个 条件遗传消融巨噬细胞内TNAP或增加血浆中TNAP活性的作用 然后在家族性高胆固醇血症的小鼠模型上进行测试。因为钙化斑块的消退 在降脂过程中会导致主动脉根部偏心性重构，我们将询问是否抑制TNAP 加用SBI-425可抑制钙化和减轻小鼠主动脉根部的不良适应性重构 动脉粥样硬化逆转过程中的模型。在测试TNAP抑制对动脉粥样硬化的治疗效果时 钙化，我们将通过监测骨骼微结构来密切关注潜在的骨骼副作用 使用微型计算机断层扫描。这个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，并确定全身性TNAP抑制或消除 表达成骨性TNAP的巨噬细胞是动脉粥样硬化的一种可行的治疗方法。这个 这项研究的结果将有助于指导未来对这种流行疾病的新疗法的开发。

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.