ABSTRACT
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.
Subject(s)
Atherosclerosis , MicroRNAs , Plaque, Atherosclerotic , Animals , Mice , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Atherosclerosis/chemically induced , Atherosclerosis/genetics , Calcineurin/metabolism , CD36 Antigens/metabolism , Cyclosporine/adverse effects , Cyclosporine/metabolism , Lipids , Macrophages , Mice, Inbred C57BL , MicroRNAs/genetics , MicroRNAs/metabolism , Plaque, Atherosclerotic/chemically induced , Plaque, Atherosclerotic/metabolismABSTRACT
Basic research for prevention and treatment of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues worldwide. In particular, multiple newly reported cases of autoimmune-related diseases after COVID-19 require further research on coronavirus-related immune injury. However, owing to the strong infectivity of SARS-CoV-2 and the high mortality rate, it is difficult to perform relevant research in humans. Here, we reviewed animal models, specifically mice with coronavirus-related immune disorders and immune damage, considering aspects of coronavirus replacement, viral modification, spike protein, and gene fragments. The evaluation of mouse models of coronavirus-related immune injury may help establish a standardised animal model that could be employed in various areas of research, such as disease occurrence and development processes, vaccine effectiveness assessment, and treatments for coronavirus-related immune disorders. COVID-19 is a complex disease and animal models cannot comprehensively summarise the disease process. The application of genetic technology may change this status.