Study uncovers mechanisms by which microRNAs drive atherogenesis in a cell-type-specific manner

Researchers at the University of Eastern Finland have uncovered potential mechanisms by which microRNAs (miRNA) drive atherogenesis in a cell-type-specific manner. Published in the Arteriosclerosis, Thrombosis, and Vascular Biology journal, the study provides novel insight into the miRNA profiles of the main cell types involved in atherosclerosis.

Atherosclerosis is the underlying cause of most cardiovascular diseases and one of the leading causes of mortality in the world. During atherosclerosis, arteries become progressively narrow and thick due to the formation of plaques containing cholesterol deposits, calcium and cells, among other components. Although the role and contribution to atherosclerosis of endothelial cells, smooth muscle cells and macrophages - the main cell types associated with disease progression in the vascular wall - has been previously described, the molecular mechanisms leading to gene expression changes during atherosclerosis in these cell types remain unknown.

In particular, the cell-type specific expression and regulation of miRNAs in the disease context has remained unexplored. MiRNAs represent one class of small non-coding RNAs that regulate the protein production by binding to messenger RNAs of protein encoding genes and this way affect cell function and disease progression.

In this study, by integrating different next generation sequencing techniques, the researchers have provided a deeper understanding of the miRNA changes in primary human endothelial cells, smooth muscle cells and macrophages under various pro-atherogenic stimuli, and discovered that the precursor forms of the miRNA (primary miRNAs) were highly expressed in a cell-type specific manner, suggesting distinct regulatory mechanisms on transcriptional level. In contrast, the large majority of mature miRNAs were common to all cell types and dominated by 2-5 abundant miRNA species.

Moreover, the researchers uncovered microRNA-messenger RNA networks through which miRNAs could drive cell-type-specific responses. Given that miRNAs play an essential role in maintaining tissue homeostasis and can be dysregulated in pathological states, miRNA therapeutics that manipulate cellular miRNA levels are essential and have already entered clinical trials. Thus, these results are fundamental for the atherosclerosis research community and could serve as the basis for future development of cell-targeted therapeutics.

This study was performed in Associate Professor Minna Kaikkonen-Määttä's research group, and it was funded by the Academy of Finland, Emil Aaltonen Foundation, the Finnish Foundation for Cardiovascular Research, Maud Kuistila Memorial Foundation, Orion Research Foundation, Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, Ella and Georg Ehrnrooth Foundation and the European Research Council (ERC).