Vascular calcification and atherosclerosis

项目总结/摘要 心血管疾病（CVD）是美国的主要死亡原因，每年的医疗总费用 估计为3510亿美元。血管钙化是一种非传统的CVD危险因素， 一般人口的发病率和死亡率增加。与其他已确定的风险因素不同， 被认为是一个可改变的因素。然而，有新的证据表明，它可能会推动发病机制， 在动脉粥样硬化斑块的消退中起重要作用。我们的数据表明 内皮细胞中组织非特异性碱性磷酸酶（TNAP）的过度表达加速了 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 冠状动脉疾病。内、外膜下常可见微钙化， 弹性膜在小鼠和人类动脉，并预测计算流体结构相互作用 (FSI)建模以重新分配内皮上的壁剪切应力。钙化可以促进 动脉粥样硬化的进一步支持是观察到低密度脂蛋白（LDL）摄取增加， 在用羟基磷灰石颗粒纹理化的表面上培养的内皮细胞。更多来自老鼠的证据 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 动脉粥样硬化和干扰斑块消退，导致主动脉根部的不适应性扩张。 我们假设钙化是动脉粥样硬化的一个可改变的因素，抑制TNAP介导的 血管钙化可能具有治疗价值。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、发展和消退过程中的作用， 并确定钙化是否是动脉粥样硬化中的活跃致病因素或仅仅是，可能是良性的， 次要反应。该项目将使用计算和体内模型来描绘血液动力学 内皮下微钙化增加LDL在动脉壁中的滞留的机制。的 巨噬细胞中TNAP的条件性基因消融或血浆中TNAP活性增加的影响 然后将在家族性高胆固醇血症的小鼠模型中进行测试。因为钙化斑块的消退 在降脂过程中可导致偏心性主动脉根部重塑，我们将询问抑制TNAP是否 SBI-425可以抑制钙化并减轻小鼠主动脉根部的适应不良重塑。 动脉粥样硬化逆转模型。在测试TNAP抑制对动脉粥样硬化的治疗效用中， 钙化，我们将通过监测骨微结构密切关注潜在的骨副作用 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 成骨的表达TNAP的巨噬细胞是动脉粥样硬化的可行治疗方法。的 这项研究的结果将有助于指导这种流行疾病的新疗法的未来发展。

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.