Proline/serine-rich coiled-coil protein 1 inhibits macrophage inflammation and delays atherosclerotic progression by binding to Annexin A2.

Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: Heidelberg : Springer-Verlag

Annexin A2* ; Atherosclerosis*/metabolism ; Coronary Artery Disease* ; Phosphoproteins*/metabolism; Animals ; Mice ; Inflammation ; Macrophages/metabolism ; Proline ; Serine ; Transcription Factors/metabolism ; Mice, Knockout, ApoE

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.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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82170474 National Natural Science Foundation of China; 2019A1515010666 Guangdong Basic and Applied Basic Research Foundation; LC2016PY002 Clinical Research Startup Program of Southern Medical University by High-level Construction Funding of Guangdong Provincial Department of Education; 2018CR051 Clinical Research Program of Nanfang Hospital, Southern Medical University

Keywords: Annexin A2; atherosclerosis; inflammation; macrophage; proline/serine-rich coiled-coil protein 1

0 (Annexin A2)
9DLQ4CIU6V (Proline)
452VLY9402 (Serine)
0 (Transcription Factors)
0 (Psrc1 protein, mouse)
0 (Phosphoproteins)

Date Created: 20230318 Date Completed: 20230323 Latest Revision: 20230330

20250114

PMC10023832

10.1002/ctm2.1220

36932468