Elizondo-Benedetto Santiago, Sastriques-Dunlop Sergio, Detering Lisa, Arif Batool, Heo Gyu Seong, Sultan Deborah, Luehmann Hannah, Zhang Xiaohui, Gao Xuefeng, Harrison Kitty, Thies Dakkota, McDonald Laura, Combadière Christophe, Lin Chieh-Yu, Kang Yeona, Zheng Jie, Ippolito Joseph, Laforest Richard, Gropler Robert J, English Sean J, Zayed Mohamed A, Liu Yongjian
medRxiv. 2023 Nov 7:2023.11.06.23298031. doi: 10.1101/2023.11.06.23298031.
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease impacting aging populations with a high mortality upon rupture. There are no effective medical therapies to prevent AAA expansion and rupture. We previously demonstrated the role of the monocyte chemoattractant protein-1 (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis in rodent AAA pathogenesis via positron emission tomography/computed tomography (PET/CT) using CCR2 targeted radiotracer Cu-DOTA-ECL1i. We have since translated this radiotracer into patients with AAA. CCR2 PET showed intense radiotracer uptake along the AAA wall in patients while little signal was observed in healthy volunteers. AAA tissues collected from individuals scanned with Cu-DOTA-ECL1i and underwent open-repair later demonstrated more abundant CCR2+ cells compared to non-diseased aortas. We then used a CCR2 inhibitor (CCR2i) as targeted therapy in our established male and female rat AAA rupture models. We observed that CCR2i completely prevented AAA rupture in male rats and significantly decreased rupture rate in female AAA rats. PET/CT revealed substantial reduction of Cu-DOTA-ECL1i uptake following CCR2i treatment in both rat models. Characterization of AAA tissues demonstrated decreased expression of CCR2+ cells and improved histopathological features. Taken together, our results indicate the potential of CCR2 as a theranostic biomarker for AAA management.
腹主动脉瘤（AAA）是一种退行性血管疾病，影响老年人群，破裂时死亡率很高。目前尚无有效的药物疗法来预防AAA的扩张和破裂。我们之前通过使用CCR2靶向放射性示踪剂Cu-DOTA-ECL1i的正电子发射断层扫描/计算机断层扫描（PET/CT），证明了单核细胞趋化蛋白-1（MCP-1）/C-C趋化因子受体2型（CCR2）轴在啮齿动物AAA发病机制中的作用。此后，我们已将这种放射性示踪剂应用于AAA患者。CCR2 PET显示患者AAA壁有强烈的放射性示踪剂摄取，而在健康志愿者中未观察到信号。从用Cu-DOTA-ECL1i扫描并随后接受开放修复的个体收集的AAA组织显示，与未患病的主动脉相比，CCR2+细胞更丰富。然后，我们在已建立的雄性和雌性大鼠AAA破裂模型中使用CCR2抑制剂（CCR2i）作为靶向治疗。我们观察到CCR2i完全预防了雄性大鼠的AAA破裂，并显著降低了雌性AAA大鼠的破裂率。PET/CT显示在两种大鼠模型中CCR2i治疗后Cu-DOTA-ECL1i摄取大幅减少。AAA组织的特征表明CCR2+细胞的表达减少，组织病理学特征得到改善。综上所述，我们的结果表明CCR2作为AAA治疗诊断生物标志物的潜力。
