LncRNA RP4-639F20.1 interacts with THRAP3 to attenuate atherosclerosis by regulating c-FOS in vascular smooth muscle cells proliferation and migration

Background and aims The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) plays the essential role in the pathogenesis of atherosclerosis (AS). Long noncoding RNAs (lncRNAs) have been reported as important regulators in a number of diseases. However, the very little is known regarding the functional role of lncRNAs in governing proliferation and migration of VSMCs and AS development. Methods Both in vitro and in vivo assays were performed to investigate the roles of lncRNA in pathophysiology of AS. Our previous lncRNA arrays revealed that lncRNA RP4-639F20.1 were significantly decreased in atherosclerotic plaques. Lentivirus overexpressing RP4-639F20.1 and lncRNA RP4-639F20.1 silencing vectors (Si-lnc-RP4-639F20.1) were constructed and transfected in VSMCs. The in vitro functions of lncRNA were analyzed by CCK-8 assays, EdU assays, scratch wound assays, Transwell assays, qRT-PCR analyses and Western blot analyses. RNA fluorescence in situ hybridization, immunoprecipitation and mRNA microarrays were used to explore the underlying mechanism. Adeno-associated-virus-9 (AAV9) overexpressing RP4-639F20.1 were constructed and injected intravenously into ApoE−/− mice to explore the role of lncRNA in vivo. Results In vitro experiments showed that lncRNA RP4-639F20.1 interacted with THRAP3 and downregulated c-FOS expression. Both augmentation of lncRNA RP4-639F20.1 expression and knockdown c-FOS inhibited the expression of MMP10 and VEGF-α in VSMCs and suppressed VSMCs proliferation and migration. In vivo experiments usingApoE−/− mice fed a high-fat diet demonstrated that lncRNA RP4-639F20.1 overexpression deterred atherosclerosis and decreased lipid contents in atherosclerotic lesions. Patients with coronary artery disease were found to have higher c-FOS levels than healthy individuals and c-FOS expression was positively correlated with the SYNTAX score of patients. Conclusions Overall these data indicated that lncRNA RP4-639F20.1/THRAP3/c-FOS pathway protects against the development of atherosclerosis by suppressing VSMCs proliferation and migration. LncRNA RP4-639F20.1 and c-FOS could represent potential therapeutic targets to ameliorate atherosclerosis-related diseases.