Abstract
TNF ligand-related molecule 1A (TL1A) is a vascular endothelial growth inhibitor to reduce neovascularization. Lack of apoE a expression results in hypercholesterolemia and atherosclerosis. In this study, we determined the precise effects of TL1A on the development of atherosclerosis and the underlying mechanisms in apoE-deficient mice. After 12 weeks of pro-atherogenic high-fat diet feeding and TL1A treatment, mouse aorta, serum, and liver samples were collected and used to assess atherosclerotic lesions, fatty liver, and expression of related molecules. We found that TL1A treatment significantly reduced lesions and enhanced plaque stability. Mechanistically, TL1A inhibited formation of foam cells derived from vascular smooth muscle cells (VSMCs) but not macrophages by activating expression of ABC transporter A1 (ABCA1), ABCG1, and cholesterol efflux in a liver X receptor-dependent manner. TL1A reduced the transformation of VSMCs from contractile phenotype into synthetic phenotypes by activating expression of contractile marker α smooth muscle actin and inhibiting expression of synthetic marker osteopontin, or osteoblast-like phenotype by reducing calcification. In addition, TL1A ameliorated high-fat diet-induced lipid metabolic disorders in the liver. Taken together, our work shows that TL1A can inhibit the development of atherosclerosis by regulating VSMC/foam cell formation and switch of VSMC phenotypes and suggests further investigation of its potential for atherosclerosis treatment.
Highlights
Atherosclerosis is one of the common causes of cardiovascular diseases, which can seriously impair human health
To determine whether TNF ligand–related molecule 1A (TL1A) can influence the development of atherosclerosis, we fed apoE2/2 mice the pro-atherogenic high-fat diet (HFD) for 12 weeks, a duration that can induce lesions substantially
Macrophage/foam cells play an important role in atherosclerosis, our results show that TL1A had little effect on monocyte/macrophage marker 2 (MOMA2) levels in aortic root (Fig. 2A)
Summary
To determine whether TL1A can influence the development of atherosclerosis, we fed apoE2/2 mice the pro-atherogenic HFD for 12 weeks, a duration that can induce lesions substantially. By completing the Alizarin Red S staining of aortic root cross-sections, we found a marked decrease of calcification-positive areas in lesion areas of TL1A-treated mice (Fig. 1E) Taken together, these results suggest that TL1A inhibits the development of atherosclerosis, enhances lesion stability, and reduces vascular calcification. We found that TL1A reduced cholesterol efflux to HDL from macrophages (Fig. 2H) Taken together, these results suggest that TL1A promotes formation of foam cells derived from macrophages by inducing CD36 expression and inhibiting ABCA1/G1 expression. The results above demonstrate that TL1A treatment reduces formation of foam cells derived from VSMCs mainly by enhancing ABCA1/G1 expression with LXRa/b activation and promoting cholesterol efflux. The results of immunofluorescent staining and Western blotting demonstrate that calcification medium induced RUNX2 expression and nuclear translocation in HASMCs, which was reduced by TL1A (Fig. 5, E–G). The results above demonstrate that TL1A inhibits vascular calcification by inactivating RUNX2 pathway both in vivo and in vitro
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