Dual action of macrophage miR‐204 confines cyclosporine A‐induced atherosclerosis

Author:

Su Jia‐Hui12,Hong Yu23,Han Cong‐Cong2,Yu Jie4,Guan Xin2,Zhu Ya‐Mei5,Wang Cheng6,Ma Ming‐Ming2ORCID,Pang Rui‐Ping2,Ou Jing‐Song78,Zhou Jia‐Guo26,Zhang Zi‐Yi2,Ban Tao5,Liang Si‐Jia126ORCID

Affiliation:

1. Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou China

2. Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou China

3. Department of Pharmacy, The First Affiliated Hospital Sun Yat‐Sen University Guangzhou China

4. Department of General Surgery, Zhujiang Hospital Southern Medical University Guangzhou China

5. Department of Pharmacology, College of Pharmacy Harbin Medical University, Heilongjiang Academy of Medical Sciences Harbin China

6. Program of Kidney and Cardiovascular Diseases, the Fifth Affiliated Hospital, Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou China

7. Division of Cardiac Surgery, The Key Laboratory of Assisted Circulation, Ministry of Health The First Affiliated Hospital, Sun Yat‐Sen University Guangzhou China

8. National‐Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases The First Affiliated Hospital, Sun Yat‐Sen University Guangzhou China

Abstract

Background and PurposeAtherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA‐204 (miR‐204) transcription. We therefore hypothesised that miR‐204 is involved in the development of CsA‐induced atherosclerosis.Experimental ApproachApoE−/− mice with macrophage‐miR‐204 overexpression were generated to determine the effects of miR‐204 on CsA‐induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR‐204 effects.Key ResultsCsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high‐fat diet‐induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE−/− mice, respectively. miR‐204 levels decreased in circulating monocytes and plaque lesions during CsA‐induced atherosclerosis. The upregulation of miR‐204 in macrophages inhibited CsA‐induced atherosclerotic plaque formation but did not affect serum lipid levels. miR‐204 limited the CsA‐induced foam cell formation by reducing the expression of the scavenger receptors SR‐BII and CD36. SR‐BII was post‐transcriptionally regulated by mature miR‐204‐5p via 3′‐UTR targeting. Additionally, nuclear‐localised miR‐204‐3p prevented the CsA‐induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR‐BII or CD36 expression restoration dampened the beneficial effects of miR‐204 on CsA‐induced atherosclerosis.Conclusion and ImplicationsMacrophage miR‐204 ameliorates CsA‐induced atherosclerosis, suggesting that miR‐204 may be a potential target for the prevention and treatment of CsA‐related atherosclerotic side effects.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Basic and Applied Basic Research Foundation of Guangdong Province

Guangzhou Municipal Science and Technology Project

Publisher

Wiley

Subject

Pharmacology

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