Restoration of miR-299-3p promotes efferocytosis and ameliorates atherosclerosis via repressing CD47 in mice.

Atherosclerotic plaque formation is largely attributed to the impaired efferocytosis, which is known to be associated with the pathologic upregulation of cluster of differentiation 47 (CD47), a key antiphagocytic molecule. By gene expression omnibus (GEO) datasets analysis, we identified that four miRNAs are aberrantly downregulated in atherosclerosis, coronary artery disease, and obesity. Of them, hsa-miR-299-3p (miR-299-3p) was predicted to target the 3'UTR of human CD47 mRNA by bioinformatics analysis. Further, we demonstrated that miR-299-3p negatively regulates CD47 expression by binding to the target sequence "CCCACAU" in the 3'UTR of CD47 mRNA through luciferase reporter assay and site-directed mutagenesis. Additionally, we found that miR-299-3p was downregulated by ~32% in foam cells in response to oxidized low-density lipoprotein (ox-LDL) stimulation, thus upregulating CD47 and contributing to the impaired efferocytosis. Whereas, restoration of miR-299-3p reversed the ox-LDL-induced upregulation of CD47, thereby facilitating efferocytosis. In high-fat diet (HFD) fed ApoE-/- mice, we discovered that miR-299-3p was downregulated thus leading to upregulation of CD47 in abdominal aorta. Conversely, miR-299-3p restoration potently suppressed HFD-induced upregulation of CD47 and promoted phagocytosis of foam cells by macrophages in atherosclerotic plaques, thereby reducing necrotic core, increasing plaque stability, and mitigating atherosclerosis. Conclusively, we identify miR-299-3p as a negative regulator of CD47, and reveal a molecular mechanism whereby the ox-LDL-induced downregulation of miR-299-3p leads to the upregulation of CD47 in foam cells thus contributing to the impaired efferocytosis in atherosclerosis, and propose miR-299-3p can potentially serve as an inhibitor of CD47 to promote efferocytosis and ameliorate atherosclerosis.

Short-term effects of snow cover manipulation on soil bacterial diversity and community composition.

Winter snow cover is a major driver of soil microbial processes in high-latitude and high-altitude ecosystems. Warming-induced reduction in snow cover as predicted under future climate scenarios may shift soil bacterial communities with consequences for soil carbon and nutrient cycling. The underlying mechanisms, however, remain elusive. In the present study, we conducted a snow manipulation experiment in a Tibetan spruce forest to explore the immediate and intra-annual legacy effects of snow exclusion on soil bacterial communities. We analyzed bacterial diversity and community composition in the winter (i.e., the deep snow season), in the transitional thawing period, and in the middle of the growing season. Proteobacteria, Acidobacteria, and Actinobacteria were dominant phyla across the seasons and snow regimes. Bacterial diversity was generally not particularly sensitive to the absence of snow cover. However, snow exclusion positively affected Simpson diversity in the winter but not in the thawing period and the growing season. Bacterial diversity further tended to be higher in winter than in the growing season. In the winter, the taxonomic composition shifted in response to snow exclusion, while composition did not differ between exclusion and control plots in the thawing period and the growing season. Soil bacterial communities strongly varied across seasons, and the variations differed in specific groups. Both soil climatic factors (i.e., temperature and moisture) and soil biochemical variables partly accounted for the seasonal dynamics of bacterial communities. Taken together, our study indicates that soil bacterial communities in Tibetan forests are rather resilient to change in snow cover, at least at an intra-annual scale.