用于评估小鼠模型中动脉粥样硬化斑块负荷的ADAMTS4特异性磁共振肽探针

ADAMTS4-Specific MR Peptide Probe for the Assessment of Atherosclerotic Plaque Burden in a Mouse Model.

作者信息

Mangarova Dilyana B, Kaufmann Jan O, Brangsch Julia, Kader Avan, Möckel Jana, Heyl Jennifer L, Verlemann Christine, Adams Lisa C, Ludwig Antje, Reimann Carolin, Poller Wolfram C, Niehaus Peter, Karst Uwe, Taupitz Matthias, Hamm Bernd, Weller Michael G, Makowski Marcus R

机构信息

From the Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany (D.B.M., J.O.K., J.B., A.K., J.M., J.L.H., C.R., M.T., B.H., M.R.M.); Department of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany (D.B.M., J.O.K., J.B., A.K., L.C.A., M.R.M.); Department of Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany (J.O.K.); Division 1.5 Protein Analysis, Federal Institute for Materials Research and Testing, Berlin, Germany (J.O.K., M.G.W.); Department of Biology, Chemistry, and Pharmacy, Institute of Biology, Freie Universität Berlin, Berlin, Germany (A.K.); Department of Veterinary Medicine, Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Freie Universität Berlin, Berlin, Germany (J.L.H.); Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany (C.V., P.N., U.K.); Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany (A.L.); DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany (A.L.); and Division of Cardiology, Massachusetts General Hospital, Harvard University, Boston, MA (W.C.P.).

出版信息

Invest Radiol. 2025 Jan 14. doi: 10.1097/RLI.0000000000001152.

DOI:10.1097/RLI.0000000000001152

PMID:39804796

Abstract

INTRODUCTION

Atherosclerosis is the underlying cause of multiple cardiovascular pathologies. The present-day clinical imaging modalities do not offer sufficient information on plaque composition or rupture risk. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is a strongly upregulated proteoglycan-cleaving enzyme that is specific to cardiovascular diseases, inter alia, atherosclerosis.

MATERIALS AND METHODS

Male apolipoprotein E-deficient mice received a high-fat diet for 2 (n = 11) or 4 months (n = 11). Additionally, a group (n = 11) receiving pravastatin by drinking water for 4 months alongside the high-fat diet was examined. The control group (n = 10) consisted of C57BL/6J mice on standard chow. Molecular magnetic resonance imaging was performed prior to and after administration of the gadolinium (Gd)-based ADAMTS4-specific probe, followed by ex vivo analyses of the aortic arch, brachiocephalic arteries, and carotid arteries. A P value <0.05 was considered to indicate a statistically significant difference.

RESULTS

With advancing atherosclerosis, a significant increase in the contrast-to-noise ratio was measured after intravenous application of the probe (mean precontrast = 2.25; mean postcontrast = 11.47, P < 0.001 in the 4-month group). The pravastatin group presented decreased ADAMTS4 expression. A strong correlation between ADAMTS4 content measured via immunofluorescence staining and an increase in the contrast-to-noise ratio was detected ( R2 = 0.69). Microdissection analysis revealed that ADAMTS4 gene expression in the plaque area was significantly greater than that in the arterial wall of a control mouse ( P < 0.001). Laser ablation-inductively coupled plasma-mass spectrometry confirmed strong colocalization of areas positive for ADAMTS4 and Gd.

CONCLUSIONS

Magnetic resonance imaging using an ADAMTS4-specific agent is a promising method for characterizing atherosclerotic plaques and could improve plaque assessment in the diagnosis and treatment of atherosclerosis.

摘要

引言

动脉粥样硬化是多种心血管疾病的根本原因。目前的临床成像方式无法提供足够的关于斑块成分或破裂风险的信息。含血小板反应蛋白基序的解聚素和金属蛋白酶4（ADAMTS4）是一种上调强烈的蛋白聚糖裂解酶，它对心血管疾病具有特异性，尤其是动脉粥样硬化。

材料与方法

雄性载脂蛋白E缺陷小鼠接受高脂饮食2个月（n = 11）或4个月（n = 11）。此外，研究了一组（n = 11）在高脂饮食的同时通过饮水服用普伐他汀4个月的小鼠。对照组（n = 10）由喂食标准饲料的C57BL/6J小鼠组成。在静脉注射基于钆（Gd）的ADAMTS4特异性探针之前和之后进行分子磁共振成像，随后对主动脉弓、头臂动脉和颈动脉进行离体分析。P值<0.05被认为具有统计学显著差异。

结果

随着动脉粥样硬化的进展，静脉注射探针后测量的对比噪声比显著增加（4个月组造影前平均值 = 2.25；造影后平均值 = 11.47，P < 0.001）。普伐他汀组的ADAMTS4表达降低。通过免疫荧光染色测量的ADAMTS4含量与对比噪声比的增加之间存在强相关性（R2 = 0.69）。显微切割分析显示，斑块区域的ADAMTS4基因表达显著高于对照小鼠的动脉壁（P < 0.001）。激光烧蚀-电感耦合等离子体质谱法证实了ADAMTS4阳性区域与Gd的强共定位。