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Int J Med Sci 2021; 18(16):3652-3664. doi:10.7150/ijms.63065 This issue Cite

Research Paper

Elimination of Ox-LDL through the liver inhibits advanced atherosclerotic plaque progression

Zhiwen Wang^1#, Xiaopeng Guo^2#, Qing Zhang¹, Gaohui Du¹, Zhuanglin Zeng^3✉, Chuansheng Zheng^2✉, Yumiao Wei^1✉

1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3. Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
#Equal contributions to this work.

✉ Corresponding authors: Yumiao Wei, MD, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Address: 1277 Jiefang Avenue, Wuhan, China, 430021. E-mail: ymwei12com. Tel/Fax: 86-27-87558314. Chuansheng Zheng, MD, PhD, Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Address: 1277 Jiefang Avenue, Wuhan, China, 430021. E-mail: hgzcsxhcom. Tel/Fax: 86-27-85353238. Zhuanglin Zeng, MD, Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Address: 1277 Jiefang Avenue, Wuhan, China, 430021. E-mail: zhuanglinzengedu.cn. Tel/Fax: 86-27-87558314. More

Abstract

Aim: 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.

Methods and Results: 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.

Conclusions: 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.

Keywords: Ox-LDL, LOX-1, Atherosclerosis, Foam Cell, Necrotic Core

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