miRNA-Mediated Regulatory Mechanisms

miRNAs have been demonstrated to regulate a variety of cellular mechanisms as inflammation, cell regeneration, or lipid metabolism, thereby contributing in different manner to the progression of atherosclerosis (Rayner et al. 2012). The canonical miRNA biogenesis starts with nuclear processing of primary miRNA transcripts by the Drosha complex into precursor miRNAs (Ha and Kim 2014). These precursors are then transported to the cytoplasm which are further processed by the RNase III enzyme Dicer yielding miRNA-miRNA* heteroduplexes (Ha and Kim 2014). The miRNA duplex is loaded into the pre-RISC and undergoes strand selection. In the mature RISC, the selected miRNA strand binds to mRNA targets triggering their translation inhibition or degradation (Fig. 1.1) (Ha and Kim 2014). In addition, miRNAs can be generated by noncanonical pathways independent of Drosha or Dicer activities, like miR-320 or miR-451 (Ha and Kim 2014). miRNAs target mRNAs primarily by pairing of miRNA seed sequences (i.e., the nucleotides 2-8 at the 5' end) and the miRNA response elements (MRE) within RNAs. Although MREs are frequently present in the 3' untranslated region (UTR) of target RNA, several miRNAs can bind to their targets by pairing to their coding regions or 5’UTRs (Helwak et al. 2013). These short seed match and incomplete base pairing between miRNA and mRNA enables a single miRNA to target up to hundreds of different RNA molecules (Friedman et al. 2009). Although miRNAs typically target mRNAs, a wide range of RNA molecules including pseudogenes, long-intergenic non-coding RNAs, ribosomal RNAs, transfer RNAs, small nuclear RNAs, and also other miRNAs has been demonstrated to be targeted by miRNAs (Helwak et al.

2013). These miRNA-mediated effects can be regulated by various factors such as abundance of miRNAs or of their targets, differential expression of miRNAs, and relative abundance of target sites (i.e., the relative number of sites within the tran- scriptome for an individual miRNA) (Arvey et al. 2010; Garcia et al. 2011). Recent studies have confirmed the relevance of novel miRNA mechanisms in atherosclerosis as, for instance, the role of coexisting miRNAs strands of a single miRNA precursor, the modulation by miRNAs sponges, and the paracrine effects of miRNAs in circulation (Fig. 1.1).

 
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