Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
International Collaboration On Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Sci Rep. 2017 Nov 20;7(1):15857. doi: 10.1038/s41598-017-16194-8.
Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.
核心聚糖（DCN）是一种富含亮氨酸的小型蛋白聚糖，可介导胶原蛋白原纤维的形成、组织和拉伸强度。腹主动脉瘤（AAA）中存在的外膜核心聚糖（DCN）减少，导致血管壁不稳定，从而使血管易于破裂。重组 DCN 融合蛋白 CAR-DCN 通过延长 C 末端工程化设计，该 C 末端包含 CAR 归巢肽，可识别发炎的血管并深入穿透血管壁。在本研究中，在小鼠模型中评估了全身性给予 CAR-DCN 在 AAA 进展和破裂中的作用。用血管紧张素 II（AngII）对载脂蛋白 E 基因敲除（ApoE-KO）小鼠输注 28 天以诱导 AAA 形成。CAR-DCN 或载体系统给药直至第 15 天。与对照组相比，CAR-DCN 治疗的小鼠因 AAA 破裂导致的死亡率明显降低。尽管载体组和 CAR-DCN 组的 AAA 发生率相似，但 CAR-DCN 组的 AAA 严重程度明显降低。组织学分析显示，与载体对照组相比，CAR-DCN 治疗可显著增加主动脉壁内的 DCN 和胶原蛋白水平。综上所述，这些结果表明，CAR-DCN 治疗通过增强主动脉壁来减轻 Ang II 诱导的 AAA 的形成和破裂。
