The implications of microRNAs (miRNAs) in cardiovascular disease have recently been recognized, representing the most rapidly evolving research field. Atherosclerosis, major cause of CVD, is a chronic disease characterized by lipid retention and vascular inflammation. Macrophages are recognized to have a unique impact on the disease progression. Within the atherosclerotic plaque macrophages respond to a large number of signals, which promote complex changes in gene transcription as well as post-transcriptional regulatory mechanisms of control of gene expression. Important players of the post-transcriptional regulatory network are the small non- coding RNAs, microRNAs, which have a demonstrated role in the control of transcriptional networks in macrophages. miR-21 is the most abundant miRNA in macrophages accounting for 42% of total miRNA content. However its role in regulating macrophage functions during atherogenesis remains unexplored. Intriguingly, miRNAs can be transferred from cell to cell by exosomes, thus facilitating the exchange of information among cells. In the context of atherosclerosis the effect of miR-21 has not been explored in light of their possible delivery, via exosomes to vascular cells such as endothelial cells (ECs) or vascular smooth muscle cells (VSMCs). Collectively, this work will define the mechanisms by which miR-21 regulates atherogenesis, will determine the paracellular actions of macrophage miR-21 in vivo on ECs or VSMCs within atherosclerotic plaques and shed insights into miR-21 role as potential therapeutic target for atherosclerosis.
The proposal main goal is to investigate the contribution miRNA-21 in the regulation atherosclerosis. The proposal will additionally investigate potential role of the transfer of this miRNA in regulating gene expression and functions of different vascular cells including endothelial cells and vascular smooth muscle cells during the progression of atherosclerosis. This work will provide critical insight into fundamental regulatory mechanisms of cardiovascular diseases including atherosclerosis.
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