Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Int J Med Sci. 2021 Sep 9;18(16):3652-3664. doi: 10.7150/ijms.63065. eCollection 2021.
In the late stage of atherosclerosis, the endothelial barrier of plaque is destroyed. The rapid deposition of oxidized lipids in the circulation leads to migration of numerous smooth muscle cells and macrophages, as well as foaming necrosis. The plaque progresses rapidly, and vulnerable plaques can easily induce adverse cardiovascular events. Here, we take the principle of gene editing to transfer the liver to express the LOX-1 receptor which is more sensitive to Ox-LDL by using AAV8 containing a liver-specific promoter. In this way, we want to explore whether the progress of advanced atherosclerosis and the stability of advanced plaque can be improved when the liver continues to clear Ox-LDL from the circulation. In order to explore the effect of the physiological and continuous elimination of Ox-LDL through the liver on advanced atherosclerosis, we chose ApoE mice in high-fat diet for 20 weeks. After 16 weeks of high-fat diet, the baseline group was sacrificed and the specimens were collected. The virus group and the control group were injected with the same amount of virus dilution and normal saline through the tail vein, and continued to feed until 20 weeks of high-fat diet, and then sacrificed to collect specimens. The results showed that LOX-1 was ectopically and functionally expressed in the liver as an Ox-LDL receptor, reducing the content of it in circulation. Compared with the control group, the degree of plaque progression in the virus group was significantly reduced, similar to the baseline group, the plaque necrosis core decreased, and the collagen fiber content increased. In addition, there are more contractile smooth muscle cells in the plaques of the virus group instead of synthetic ones, and the content of macrophages was also reduced. These data suggested that the virus group mice have greatly increased advanced plaque stability compared with the control group mice. Due to the destruction of endothelial barrier in advanced plaques, rapid deposition of Ox-LDL can result in fast plaque progression, increased necrotic cores, and decreased stability. Our research shows that the use of AAV8 through gene editing allows the liver to express LOX-1 receptors that are more sensitive to Ox-LDL, so that it can continue to bind Ox-LDL in the circulation and exploit the liver's strong lipid metabolism ability to physiologically clear Ox-LDL, which can inhibit the rapid progress of advanced plaque and increase the stability of plaque.
在动脉粥样硬化的晚期，斑块的内皮屏障被破坏。循环中氧化脂质的快速沉积导致大量平滑肌细胞和巨噬细胞迁移，并发生泡沫状坏死。斑块迅速进展，易损斑块很容易引发不良心血管事件。在这里，我们利用 AAV8 携带肝特异性启动子，将肝脏转导为表达对 Ox-LDL 更敏感的 LOX-1 受体，以此来探讨肝脏持续从循环中清除 Ox-LDL 是否能改善晚期动脉粥样硬化的进展和晚期斑块的稳定性。为了探索肝脏通过生理和持续清除 Ox-LDL 对晚期动脉粥样硬化的影响，我们选择了高脂饮食喂养 20 周的 ApoE 小鼠。在高脂饮食喂养 16 周后，处死基线组并采集标本。病毒组和对照组通过尾静脉注射等量的病毒稀释液和生理盐水，继续喂养至 20 周高脂饮食后处死，采集标本。结果显示，LOX-1 作为 Ox-LDL 受体在肝脏中异位和功能性表达，降低了循环中的含量。与对照组相比，病毒组的斑块进展程度明显降低，与基线组相似，斑块坏死核心减少，胶原纤维含量增加。此外，病毒组斑块中的收缩型平滑肌细胞增多，而合成型平滑肌细胞减少，巨噬细胞含量也减少。这些数据表明，与对照组相比，病毒组小鼠的晚期斑块稳定性大大提高。由于晚期斑块内皮屏障的破坏，Ox-LDL 的快速沉积可导致斑块快速进展、坏死核心增加、稳定性降低。我们的研究表明，通过基因编辑使用 AAV8 可使肝脏表达对 Ox-LDL 更敏感的 LOX-1 受体，使其能够继续结合循环中的 Ox-LDL，并利用肝脏强大的脂质代谢能力进行生理性清除 Ox-LDL，从而抑制晚期斑块的快速进展，增加斑块的稳定性。
