Use of il-18 inhibitors for the treatment and/or prevention of atherosclerosis
An atherosclerosis, inhibitor technology, applied in the field of vascular disease, can solve the problems of lack of Ig region, lack of binding or neutralization of IL-18, etc.
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Embodiment 1
[0140] Example 1 : IL-18 inhibitor protects endothelial cell death from oxidized lipoprotein (oxLDL)
[0141] Cultured human umbilical vein endothelial cells (HUVEC) were exposed to oxidized lipoproteins for 16 h in the presence or absence of IL-18-binding protein or anti-IL-18 antibody. Such as figure 1 As shown, 83% of HUVECs died after exposure to oxidized lipoproteins. However, incubation with IL-18BP or anti-IL-18 antibody can make almost all the cells survive. No cell death was observed in incubation with IL-18BP. The survival rate of cells cultured with anti-IL-18 antibody was 89%.
[0142] This experiment clearly demonstrates the protective effect of two different IL-18 inhibitors on cell death due to apoptosis in atherosclerotic plaques.
Embodiment 2
[0143] Example 2 : Expression of IL-18 protein and its endogenous inhibitor IL-18BP in atherosclerotic plaques
[0144] Protein extracts from 12 carotid atherosclerotic arteries and 5 normal control arteries were analyzed by Western blot. IL-18 protein, including the activated form, is highly expressed in all atherosclerotic plaques, whereas in normal arteries ( figure 2 ) with little or no expression detected. Lanes 1 to 4 are samples from atherosclerotic plaques, and lanes 5 to 7 are samples from normal arteries. Interestingly, the detection of the activated form of IL-18 seems to be related to that involved in IL-18 processing ( figure 2 Front row) related to the expression of the activated form of caspase-1. Significant expression of IL-18 receptor protein (ie, the α chain) was also detected in all atherosclerotic plaques, compared with normal arteries ( figure 2 Second row) was only expressed at a very low level. In addition, although expression levels are heter...
Embodiment 3
[0145] Example 3 : Cellular localization of IL-18 protein and its endogenous inhibitor IL-18BP in atherosclerotic plaques
[0146] To determine the cellular localization of IL-18 protein and IL-18BP, immunohistochemical studies were performed on 6 carotid atherosclerotic plaques. Such as figure 2 As shown, IL-18 is mainly expressed in macrophages, and these cells may be the main source of IL-18 in plaques (not shown). These areas also had large numbers of CD3-positive lymphocytes. However, T lymphocytes do not appear to be directly involved in IL-18 production. Some intimal smooth muscle cells and occasionally endothelial cells also express IL-18. The difference is that IL-18BP was significantly expressed in plaque microvessels and endothelial cells on the luminal surface, although all blood vessels did not express it. Relatively low and more heterogeneous IL-18BP expression was also detected in some macrophage-rich regions, mainly extracellular.
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