Background Atherosclerosis (AS), the main pathological basis of life‐threatening cardiovascular disease, is essentially caused by chronic macrophage inflammation. Overexpression of proline/serine‐rich coiled‐coil protein 1 (PSRC1) reduces macrophage inflammatory responses and delays AS development. However, the exact mechanism of PSRC1 is unclear. Methods Proteins interacting with PSRC1 were screened by proteomics in RAW264.7 cells, followed by RT‒qPCR, immunoprecipitation and immunofluorescence to explore the specific mechanistic pathways affecting inflammation. CRISPR‒Cas9 constructs for PSRC1−/−ApoE−/−(DKO) mice and high‐fat diet‐fed ApoE−/− and DKO mice were used for AS models for in vivo experiments. Upstream transcription factors of PSRC1 were predicted by ATAC‐seq, ChIP‐seq and UCSC, and the regulatory mechanism was verified by ChIP‒qPCR and dual luciferase assays. Peripheral blood serum and monocytes were collected from coronary artery disease (CAD) patients and non‐CAD patients. Results Increased binding of ANXA2 to PSRC1 in macrophages under oxidized low‐density lipoprotein stimulation and decreased release of ANXA2 to the extracellular compartment were observed. Knockdown of ANXA2 in AS model mice delayed AS progression. Knockdown of ANXA2 in DKO mice reversed the AS‐promoting effect of PSRC1 knockdown. Mechanistically, ANXA2 promotes STAT3 phosphorylation, which in turn promotes inflammatory responses. In addition, SP1 is a PSRC1 upstream repressive transcription factor, and the SP1 inhibitor mithramycin (Mith) elevated PSRC1 expression and exerted anti‐AS effects in AS model mice. Patients with CAD had considerably greater serum levels of ANXA2 than those without CAD, and Mith reduced the secretion of ANXA2 in peripheral blood monocytes of CAD patients. Conclusion In macrophages, PSRC1 can interact with ANXA2 to inhibit its extracellular release and delay AS development. SP1 is an upstream transcription factor of PSRC1 and inhibits the transcription of PSRC1. The SP1 inhibitor Mith can elevate PSRC1 levels and slow AS progression while reducing ANXA2 release from monocytes in CAD patients. Mith is expected to be a new agent for AS treatment.

Long noncoding RNAs (lncRNAs) play an important role in the entire progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induce Specifically (LEPIS). The expression of LEPIS and its potential target tropomodulin 4 (TMOD4) in the liver of ApoE-/- mice fed a high-fat diet was increased. An ApoE-/- mouse model with the overexpression of LEPIS or TMOD4 in liver was established, and we found that both LEPIS and TMOD4 increased the burden of atherosclerosis and reduced hepatic cholesterol levels. Further study revealed that LEPIS and TMOD4 affect the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein, was found to be recruited from the nucleus to the cytoplasm topromote the expression of TMOD4. These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for hepatic cholesterol homeostasis and atherosclerosis.

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