Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Mol Imaging Biol. 2018 Jun;20(3):448-456. doi: 10.1007/s11307-017-1141-3.
Dysregulation of sphingosine 1-phosphate receptor 1 (S1PR1) signaling contributes to inflammation-related pathophysiological changes in cardiovascular diseases including atherosclerosis (AS). S1PR1-targeting compounds significantly reduce lesion size in murine models of AS. Therefore, characterization of S1PR1 expression in vitro and in vivo in atherosclerotic plaque could enable mechanistic studies and inform S1PR1 targeted therapies.
H&E staining and immunostaining studies were performed on variably diseased human femoral endarterectomy plaque specimens, as well as mouse aortic sections from ApoE mice maintained on a high-fat diet (AS mice). In vitro autoradiography study in human femoral plaques was used to confirm the tracer specificity. Micro positron emission tomography (PET) and ex vivo autoradiography studies were conducted in AS mice and their controls using a S1PR1-specific radioligand [C]TZ3321 for in vivo and ex vivo quantification of S1PR1 expression in mouse aortic plaques.
Increased S1PR1 expression was observed in areas of human femoral endarterectomy plaque specimens with foam cell accumulation compared with control tissue; in vitro autoradiography study indicated that SEW2781, a S1PR1 compound was able to reduce the uptake of [C]TZ3321 by 56 %. S1PR1 levels were also upregulated in AS mouse aortic plaques. MicroPET data showed the aorta-to-blood tracer uptake ratio in AS mice was approximately 20 % higher than that in controls. Autoradiographic study also revealed elevated tracer accumulation in AS mouse aorta.
Upregulated S1PR1 expression in human and mouse atherosclerotic plaques was successfully identified by immunostaining and radioligand-based methods. This data demonstrates that [C]TZ3321 PET provides great promise in imaging S1PR1 expression in atherosclerotic plaques.
鞘氨醇 1-磷酸受体 1（S1PR1）信号的失调导致心血管疾病（包括动脉粥样硬化（AS））中的炎症相关病理生理变化。S1PR1 靶向化合物可显著减少 AS 小鼠模型中的病变大小。因此，对动脉粥样硬化斑块中 S1PR1 的体外和体内表达进行特征描述，可使机制研究能够实现，并为 S1PR1 靶向治疗提供信息。
对不同病变的人股动脉内膜切除术斑块标本以及高脂饮食（AS 小鼠）饲养的 ApoE 小鼠主动脉切片进行 H&E 染色和免疫染色研究。对人股动脉斑块进行的体外放射自显影研究用于确认示踪剂的特异性。对 AS 小鼠及其对照小鼠进行微正电子发射断层扫描（PET）和离体放射自显影研究，使用 S1PR1 特异性放射性配体 [C]TZ3321 对小鼠主动脉斑块中 S1PR1 的表达进行体内和离体定量。
与对照组织相比，人股动脉内膜切除术斑块标本中泡沫细胞堆积区域观察到 S1PR1 表达增加；体外放射自显影研究表明，S1PR1 化合物 SEW2781 能够降低 [C]TZ3321 的摄取 56%。AS 小鼠主动脉斑块中的 S1PR1 水平也上调。微 PET 数据显示，AS 小鼠主动脉与血液示踪剂摄取比对照小鼠高约 20%。放射自显影研究还显示 AS 小鼠主动脉示踪剂积累增加。
通过免疫染色和放射性配体方法成功鉴定了人源和鼠源动脉粥样硬化斑块中 S1PR1 的上调表达。该数据表明，[C]TZ3321 PET 在动脉粥样硬化斑块中 S1PR1 表达的成像中具有很大的应用前景。
