Institute for Heart and Lung Health, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Cell Death Dis. 2011 Sep 8;2(9):e209. doi: 10.1038/cddis.2011.88.
Granzyme B (GZMB) is a proapoptotic serine protease that is released by cytotoxic lymphocytes. However, GZMB can also be produced by other cell types and is capable of cleaving extracellular matrix (ECM) proteins. GZMB contributes to abdominal aortic aneurysm (AAA) through an extracellular, perforin-independent mechanism involving ECM cleavage. The murine serine protease inhibitor, Serpina3n (SA3N), is an extracellular inhibitor of GZMB. In the present study, administration of SA3N was assessed using a mouse Angiotensin II-induced AAA model. Mice were injected with SA3N (0-120 μg/kg) before pump implantation. A significant dose-dependent reduction in the frequency of aortic rupture and death was observed in mice that received SA3N treatment compared with controls. Reduced degradation of the proteoglycan decorin was observed while collagen density was increased in the aortas of mice receiving SA3N treatment compared with controls. In vitro studies confirmed that decorin, which regulates collagen spacing and fibrillogenesis, is cleaved by GZMB and that its cleavage can be prevented by SA3N. In conclusion, SA3N inhibits GZMB-mediated decorin degradation leading to enhanced collagen remodelling and reinforcement of the adventitia, thereby reducing the overall rate of rupture and death in a mouse model of AAA.
颗粒酶 B（GZMB）是一种促凋亡的丝氨酸蛋白酶，由细胞毒性淋巴细胞释放。然而，GZMB 也可以由其他细胞类型产生，并能够切割细胞外基质（ECM）蛋白。GZMB 通过一种细胞外的、与穿孔素无关的机制，涉及 ECM 切割，促进腹主动脉瘤（AAA）的形成。鼠丝氨酸蛋白酶抑制剂 Serpina3n（SA3N）是 GZMB 的细胞外抑制剂。在本研究中，使用小鼠血管紧张素 II 诱导的 AAA 模型评估了 SA3N 的给药情况。在泵植入前，给小鼠注射 SA3N（0-120μg/kg）。与对照组相比，接受 SA3N 治疗的小鼠主动脉破裂和死亡的频率显著降低，呈剂量依赖性。与对照组相比，接受 SA3N 治疗的小鼠主动脉中，蛋白聚糖decorin 的降解减少，而胶原蛋白密度增加。体外研究证实，decorin 可调节胶原间距和原纤维形成，可被 GZMB 切割，而其切割可被 SA3N 阻止。总之，SA3N 抑制 GZMB 介导的 decorin 降解，导致胶原重塑和外膜增强，从而降低 AAA 小鼠模型的总体破裂和死亡速率。
