Maliheh Nazari Jahantigh
Institute for Cardiovascular Prevention - LMU, Germany
Scientific Tracks Abstracts: J Clin Exp Cardiolog
Atherosclerosis is the main cause of cardiovascular disease that are number one killer worldwide. Macrophage dysfunction contributes to the progression of atherosclerosis and microRNAs, negative regulators of gene expression, mediate macrophage function upon activation. miR-147 is upregulated in inflammatory macrophages as well as murine and human atherosclerotic plaques, while it is downregulated in peripheral monocytes from patients with coronary artery disease. However, the role of macrophage-miR-147 in atherosclerosis is yet unknown. To study that, we generated a mouse line with a deletion of the miR-147 gene in myeloid cell line, Apoe-/-LysMcreMir147flox/flox (M-Mir147-/-), and together with Apoe-/-LysMcreMir147+/+ (M-Mir147+/+) mice fed them a high cholesterol diet (HCD) for 12 wks. miR-147 deficiency in macrophages increased atherosclerosis in M-Mir147-/- versus M-Mir147+/+ mice. The increased lesion size was associated with enlarged necrotic core area, increased lesional macrophage content, increased cell death, and impaired clearance of apoptotic cells by macrophages. The effects of miR-147 deletion on proteome of inflammatory macrophages was studied by mass spectrometry in vitro and suggests that energy metabolism and Akt/mTOR signaling are the main targets of miR-147 in inflammatory macrophages. MiR-147 interactome was studied in inflammatory macrophages from M(tAgo2)-Mir147-/- and M(tAgo2)-Mir147+/+ mice, which expresses a tagged Ago2 gene following Cre recombinase activity, using an in vitro tAgo2 immunoprecipitation assay followed by RNA sequencing. Integrated analysis of interactome and proteome data suggested Tomm6, Pdk3, and Pim1 as potential targets of miR-147 in inflammatory macrophages. Our results indicate that macrophagemiR- 147 plays a protective role against atherosclerosis probably by improving macrophage function under inflammatory condition.