Dual-probe molecular MRI for the in vivo characterization of atherosclerosis in a mouse model: Simultaneous assessment of plaque inflammation and extracellular-matrix remodeling
Dual-probe molecular MRI for the in vivo characterization of atherosclerosis in a mouse model: Simultaneous assessment of plaque inflammation and extracellular-matrix remodeling
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DOI：
10.1038/s41598-019-50100-8
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发表时间：
2019-09-25
影响因子：
4.6
通讯作者：
Makowski, Marcus R.
中科院分区：
文献类型：
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作者：
Reimann, Carolin;Brangsch, Julia;Makowski, Marcus R.
分子磁共振成像是一种有前途的体内模式，检测和量化动脉粥样硬化的形态和分子血管壁的变化。不同分子生物标志物的组合可改善患者的风险分层。本研究旨在探讨在进行性动脉粥样硬化小鼠模型和治疗反应中，通过双探针分子MRI同时可视化和定量斑块负荷和炎症活性的可行性。在对头臂动脉进行MRI之前，对纯合子载脂蛋白E基因敲除小鼠（ApoE（-/-））喂食高脂饮食（HFD）长达4个月。为了评估对治疗的反应，给予相同持续时间的他汀类药物。在给予弹性蛋白特异性钆基和巨噬细胞特异性氧化铁基探针之前和之后进行MR成像。在体内MRI之后，使用组织学、免疫组织化学、电感耦合质谱法和激光电感耦合质谱法分析样品。在动脉粥样硬化斑块中，弹性纤维的斑块内表达和炎症活动没有直接联系。虽然弹性蛋白特异性探针在HFD四个月后在晚期动脉粥样硬化斑块中表现出最高的积累，但基于氧化铁的探针在HFD两个月后在早期动脉粥样硬化斑块中表现出最高的积累。弹性蛋白和氧化铁探针的体内测量与离体组织病理学良好一致（Elastica-van-Giesson染色：y = 298.2 ± 5.8，R-2 = 0.83，p < 0.05; Perls普鲁士蓝染色：y = 834.1 ± 0.67，R-2 = 0.88，p < 0.05）。弹性蛋白探针的对比噪声比（CNR）测量与ICP-MS具有良好的一致性（y = 0.11x-11.3，R-2 = 0.73，p < 0.05）。晚期动脉粥样硬化斑块显示CNR和钆浓度最强的增加（p < 0.05）。钆探头不影响氧化铁探头的可视化，反之亦然。这项研究证明了通过双探针分子MRI同时评估进行性动脉粥样硬化斑块负荷和炎症活性的可行性。在单次扫描中对不同MR生物标志物的体内检测和定量可能有助于改善动脉粥样硬化病变的表征。
Molecular MRI is a promising in-vivo modality to detect and quantify morphological and molecular vessel-wall changes in atherosclerosis. The combination of different molecular biomarkers may improve the risk stratification of patients. This study aimed to investigate the feasibility of simultaneous visualization and quantification of plaque-burden and inflammatory activity by dual-probe molecular MRI in a mouse-model of progressive atherosclerosis and in response-to-therapy. Homozygous apolipoprotein E knockout mice (ApoE(-/-)) were fed a high-fat-diet (HFD) for up to four-months prior to MRI of the brachiocephalic-artery. To assess response-to-therapy, a statin was administered for the same duration. MR imaging was performed before and after administration of an elastin-specific gadolinium-based and a macrophage-specific iron-oxide-based probe. Following in-vivo MRI, samples were analyzed using histology, immunohistochemistry, inductively-coupled-mass-spectrometry and laser-inductively-coupled-mass-spectrometry. In atherosclerotic-plaques, intraplaque expression of elastic-fibers and inflammatory activity were not directly linked. While the elastin-specific probe demonstrated the highest accumulation in advanced atherosclerotic-plaques after four-months of HFD, the iron-oxide-based probe showed highest accumulation in early atherosclerotic-plaques after two-months of HFD. In-vivo measurements for the elastin and iron-oxide-probe were in good agreement with ex-vivo histopathology (Elastica-van-Giesson stain: y = 298.2 + 5.8, R-2 = 0.83, p < 0.05; Perls' Prussian-blue-stain: y = 834.1 + 0.67, R-2 = 0.88, p < 0.05). Contrast-to-noise-ratio (CNR) measurements of the elastin probe were in good agreement with ICP-MS (y = 0.11x-11.3, R-2 = 0.73, p < 0.05). Late stage atherosclerotic-plaques displayed the strongest increase in both CNR and gadolinium concentration (p < 0.05). The gadolinium probe did not affect the visualization of the iron-oxide-probe and vice versa. This study demonstrates the feasibility of simultaneous assessment of plaque-burden and inflammatory activity by dual-probe molecular MRI of progressive atherosclerosis. The in-vivo detection and quantification of different MR biomarkers in a single scan could be useful to improve characterization of atherosclerotic-lesions.