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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Dual action of macrophage miR-204 confines cyclosporine A-induced atherosclerosis
Jia-Hui Su1,2, Yu Hong2,3, Cong-Cong Han2
1Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Background And Purpose:
Atherosclerosis 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 Approach:
ApoE-/- 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 Results:
CsA 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 Implications:
Macrophage 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.
Insights
MicroRNA-204 (miR-204) in macrophages can reduce cyclosporine A (CsA)-induced atherosclerosis by targeting SR-BII and CD36. This suggests miR-204 as a potential therapeutic target for CsA-related cardiovascular side effects.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Cyclosporine A (CsA) is associated with atherosclerosis post-transplantation, but its mechanisms are unclear.
- Calcineurin/NFAT pathway inhibition by CsA may promote atherosclerosis by reducing microRNA-204 (miR-204).
- This study investigates the role of miR-204 in CsA-induced atherosclerosis.
Purpose of the Study:
- To determine the effect of miR-204 on CsA-induced atherosclerosis.
- To elucidate the molecular targets and mechanisms through which miR-204 influences CsA-induced atherogenesis.
Main Methods:
- ApoE knockout mice with macrophage-specific miR-204 overexpression were utilized.
- Luciferase reporter assays and ChIP-sequencing were employed to identify miR-204 targets.
- Atherosclerotic lesion size, lipid levels, and foam cell formation were assessed.
Main Results:
- CsA exacerbated atherosclerosis in mice, correlating with decreased miR-204 levels in monocytes and plaques.
- Overexpression of miR-204 in macrophages inhibited CsA-induced plaque formation and foam cell development.
- miR-204 targeted SR-BII and CD36, with miR-204-5p regulating SR-BII post-transcriptionally and miR-204-3p inhibiting CD36 transcription.
Conclusions:
- Macrophage miR-204 demonstrates a protective role against CsA-induced atherosclerosis.
- miR-204 acts by suppressing SR-BII and CD36 expression, thereby limiting foam cell formation.
- miR-204 represents a potential therapeutic target for mitigating CsA-associated cardiovascular complications.
