TL1A Inhibits Atherosclerosis In ApoE Deficient Mice By Regulating The Phenotype Of Vascular Smooth Muscle Cells

TNF ligand-related molecule 1A（TL1A）is a vascular endothelial cell growth inhibitor and plays an important role in inhibiting neovascularization and tumorigenesis.However,TL1A is highly expressed in human aortic plaques.Deficiency of apolipoprotein E（apoE）can cause hypercholesterolemia and atherosclerosis.In this study,we determined the precise effects and potential molecular mechanisms of TL1A on the development of atherosclerosis in apoE knockout(apoE^-/-)mice.We randomly divided apoE^-/-mice into 2 groups.Mice were then fed pro-atherogenic high-fat diet（HFD,21%fat,0.5%cholesterol）,accompanied by intraperitoneal injection of TL1A recombinant protein for 12 weeks.After the experiment,we collected mouse aorta,liver and serum samples to determine atherosclerosis,fatty liver and expression of related molecules.In vitro,we utilized mouse peritoneal macrophages,human aortic vascular smooth muscle cells（VSMCs）and human hepatoma cell line Hep G2 cells to investigate the molecular mechanisms of TL1A affecting atherosclerosis.We found TL1A treatment substantially reduced lesions and enhanced plaque stability.Mechanistically,TL1A treatment significantly inhibited formation of foam cells derived from VSMCs,but not macrophages,by activating the adenosine triphosphate binding cassette transporter A1（ATP-binding cassette transporter A1,ABCA1）,ABCG1 and reverse cholesterol transport in a liver X receptor（LXR）-dependent manner.Furthermore,TL1A significantly reduced the transformation of VSMCs from contractile to proliferative phenotype by activating the expression of smooth muscle cell contractile phenotype markers,α-smooth muscle actin（α-SMA）and smooth muscle protein 22α（SM22α）,and inhibiting synthetic marker osteopontin（OPN）,or osteoblast-like phenotype by reducing vascular calcification.In addition,our results demonstrate that TL1A improved HFD-induced liver lipid accumulation mainly by promoting liver lipid hydrolysis and fatty acids oxidation,which also contributes to the anti-atherogenic properties of TL1A.Taken together,our study demonstrates that TL1A inhibits the development of atherosclerosis by regulating the formation of VSMC/foam cells and VSMC phenotypic switching while blocking HFD-induced liver lipid accumulation,suggesting TL1A may function as a potential strategy for the treatment of atherosclerosis.