TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells

Abstract

TNF ligand-related molecule 1A (TL1A) is a vascular endothelial growth inhibitor to reduce neovascularization. Lack of ApoE 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 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 ATP-binding cassette transporter A1 (ABCA1), ABCG1 and cholesterol efflux in the 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 the further investigation on its potential for atherosclerosis treatment.

Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways

“…To analyze NF-κB translocation, RAW264.7 cells were cultured on coverslips in a 48-well plate. After treatment, cells were conducted by immunofluorescent staining [ 27 ].…”

“…After collection, blood samples were kept at room temperature for 2 h, then centrifuged for 20 min at 2000 rpm . Serum was transferred into a new test tube and determined aspartate aminotransferase (AST), creatinine (CREA), urea nitrogen (UREA), lactate dehydrogenase (LDH), and hydroxybutyrate dehydrogenase (HBDH) levels using automatic biochemical analyzer (Hitachi, Tokyo, Japan) [ 27 ].…”

“…Liver, kidney, spleen, and cardiac tissues were fixed with 10% formalin, dehydrated, and embedded in paraffin for preparation of 5-μm section. Tissue sections were conducted using HE staining, the slides were observed under a Zeiss microscope, and the images were photographed [ 27 ].…”

Liver kinase B1 inhibits smooth muscle calcification via high mobility group box 1

“…As mentioned earlier, the inflammatory response promotes calcification [ 5 , 39 , 40 ], whereas osteogenic differentiation is an indicator of calcification [ 41 , 42 ]. TNF ligand-related molecule 1A inhibits vascular calcification by inhibiting osteogenic differentiation [ 43 ]. Moreover, the G protein signaling pathway could be implicated in the osteogenic differentiation of VSMCs during vascular calcification [ 44 ].…”

The relationship between TNF-like protein 1A and coronary artery aneurysms in children with Kawasaki disease

“…It has been shown that the levels of TL1A were signi cantly increased in patients with acute coronary syndrome, and associated with both endothelial dysfunction and coronary atherosclerosis [11] . Recent studies have shown that TL1A promotes foam cell formation in vitro by regulating the levels of low-density lipoprotein and cholesterol [9] , and it switches vascular smooth muscle cell phenotypes to participate in the development of atherosclerosis in the mouse models for apolipoprotein E-de cient atherosclerosis [18] . Here we found that the levels of TL1A in the acute phase of KD patients was signi cantly higher than those in FC and HC group, indicating that TL1A might be act as a proin ammatory factor in the vasculitis of KD.…”