Abstract
Aim: Chitinase 3-like 1 (CHI3L1) has the potential to prompt proliferation and angiogenic formation. Interleukin-13 receptor α2 (IL-13Rα2) was regarded as a receptor of CHI3L1; however, it is unknown whether CHI3L1 adjusts the neovascularization in late atherosclerotic lesions of apoE−/− mice via IL-13Rα2.Methods: Silicone collars were placed around one of the common carotid arteries of apoE−/− mice fed with a high-fat diet. The mice were further injected with Ad.CHI3L1 alone or Ad.CHI3L1 + Ad.IL-13Rα2 shRNA through the caudal vein. The plaque areas in the whole aorta and aortic root were evaluated by Oil Red O staining and H&E staining. The contents of CD31, CD42b, and collagen in carotid plaques were investigated by immunohistochemistry and Masson trichrome staining. The role of CHI3L1 in migration and tube formation of human umbilical vein endothelial cells (HUVECs) was determined by transwell and Matrigel tests. The effect of CHI3L1 on the expression of AKT and extracellular signal-regulated kinase (ERK) was evaluated with the Western blot.Results: The plaque loads in the aorta were significantly more extensive in apoE−/− mice injected with Ad.CHI3L1 than those with Ad.CHI3L1 + Ad.IL-13Rα2 shRNA. CHI3L1 significantly increased the contents of CD31 and CD42b and decreased the element of collagen in late-stage atherosclerotic lesions of the carotid arteries. The effects of CHI3L1 on migration, tube formation, and upregulation of phospho-AKT and phospho-ERK of HUVECs were prohibited by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) as well as IL-13Rα2 shRNA.Conclusion: To some extent, CHI3L1 promotes migration and tube formation of HUVECs and neovascularization in atherosclerotic plaques possibly mediated by IL-13Rα2 through AKT and ERK signal pathways.
Highlights
Atherosclerosis is a complex and multifactorial pathology occurred in arterial walls
The effects of Chitinase 3-like 1 (CHI3L1) on migration, tube formation, and upregulation of phospho-AKT and phosphoERK of human umbilical vein ECs (HUVECs) were prohibited by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) as well as IL-13Rα2 shRNA
The results of H&E staining showed that the area of atherosclerotic plaques in cross-sections of the aortic root was more extensive in Ad.CHI3L1 group than that in Ad.CHI3L1 + IL-13Rα2 shRNA group (45.5 ± 0.51% vs. 40.3 ± 0.79%, p = 0.001), there was no statistically significant difference between Ad.CHI3L1 group and control (45.5 ± 0.51% vs. 45.7 ± 0.70%, p > 0.05) (Figures 1B,D)
Summary
Atherosclerosis is a complex and multifactorial pathology occurred in arterial walls. It has been demonstrated that IL-13Rα2 was one of the membrane receptors for CHI3L1 (He et al, 2013), and the function of CHI3L1 adjusting cell apoptosis, TGF-β1 production, and several signal pathways, including macrophage mitogen-activated protein kinase (MAPK), protein kinase B/AKT, and Wnt/β-catenin, was mediated by IL-13Rα2dependent mechanisms (Lee et al, 2016; Abd El-Fattah et al, 2018; Zhou et al, 2018). It is well-known that the proliferation and migration of endothelial cells (ECs) are essential for angiogenesis in atherosclerotic plaques. Given the proangiogenic role of CHI3L1 in various tumor cells, it is necessary to understand whether CHI3L1 has a similar role in adjusting tube formation of human umbilical vein ECs (HUVECs) and neovascularization in late-stage atherosclerosis
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