**6. MicroRNAome of VSMC**

on the same mRNA or many different mRNAs, and a single mRNA can be under stringent but redundant control of several miRNAs. Another difference is the location of target sites on mRNAs. In eukaryotes miRNA target sites are in the 3'-UTRs of the mRNAs. In plants, target

miRNAs are predicted to target about 60% of protein coding transcripts [12, 42, 43]. At present the number of miRNA sequences deposited in miRBase (Release 16) include over 15,000 miRNA loci, expressing over 17,000 distinct mature miRNA sequences from 142 species [44]. Moreover, recent appreciation in miRNA research in eukaryotes implicates that these key gene expression regulators control various biological processes as diverse as cell proliferation, cell differentiation, apoptosis, and stem cell division particularly in mammalian development [38-40, 45]. In spite of tremendous advances in miRNA research, the role of miRNAs in physiological and pathophysiological processes is just emerging. Recent miRNA expression studies demonstrate miRNAs in cardiovascular development [46], brain development [47], viral infection [48], metabolism [29], different types cancer, neurologic and cardiovascular diseases [22, 25-32] suggesting link between miRNAs and wide range of tissue development and diseases. In effect, miRNAs are considered as *trans*-acting gene regulatory molecules, similar to and as important as transcription factors in the control of gene expression [49]. Although miRNAs are considered to act as intracellular RNAs to control gene expression at posttranscriptional level, recent studies have detected miRNAs in circulating blood and in cell

sites are normally in the coding region but they can be present in the 3'-UTRs.

culture medium indicating they may be useful as biomarkers of disease [50, 51].

**5. The pathway of miRNA biogenesis and gene silencing**

The transcription of miRNAs depends on their location within the genome. Most of the miRNA genes are located throughout the genome in introns, exons and intergenic regions with many miRNAs produced from clusters of coexpressed genes. Some miRNA transcription depends on same RNA polymerase II promoters that drive the transcription of mRNAs. miRNA genes located in intronic regions that includes half of known miRNAs genes often depend on the expression of host gene [52, 53]. Some miRNA genes with independent promoters are tran‐ scribed from their own RNA polymerase II promoters. Additionally a small number of miRNAs genes are transcribed by RNA polymerase III. Those miRNAs organized in clusters for example, miRNA-17-92-family, share the same transcriptional regulation and are grouped together in one cluster on a single unprocessed transcript and expressed together [54].

The process of miRNA biogenesis starts in the nucleus as depicted in the following Figure [12, 31, 32]. miRNAs are transcribed as hundreds or thousands of base long large primary miRNA species (pri-miRNA) by RNA polymerase II or RNA polymerase III. These pri-miRNA transcripts fold into a stem loop or hairpin structures with capped 5' end and polyadenylated

**4. Biogenesis of miRNAs**

150 Current Trends in Atherogenesis

miRNAs are relatively new regulatory molecules that are identified about a decade ago and demonstrated to have regulatory role in every organism and in every biological functions influencing normal biology and disease process. Once again, oncology research is in the leading position in understanding miRNA involvement in human diseases. Although most of the miRNA knowledge is coming from cancer research, during the past few years their role in other systems and diseases are emerging and rapidly being evaluated with new technologies such as deep sequencing. It is not surprising that interest in miRNA is also on the raise in cardiovascular research field. Literature on the roles and functions of miRNAs in normal cardiovascular development and in vascular pathologies is escalating [32, 46, 56-60]. Further‐ more, importance of miRNAs in the regulation of VSMC development and phenotypic modification, and response to injury is swiftly being explored because VSMC proliferation and migration are important events in vascular proliferative diseases. Here we will summarize recent updates on the significance of miRNAs in VSMCs and their role in phenotypic modu‐ lation of VSMC, thus to vascular proliferative diseases [32, 57-60]. Most of the knowledge of VSMC miRNAs is coming from culture cells, animal models and blood samples of cardiovas‐ cular disease patients.
