**1. Introduction**

Although until recently it is presumed that the greater portion of the genome has no biological role, the current advances in genome research and RNA biology have provided evidence indicating that a large section of the human and most eukaryotic genome is transcribed as nonprotein-coding RNAs or non-coding RNAs (ncRNAs)[1,2]. Only about 2% of the eukaryotic genome sequence codes for protein encoding genes and the remaining so called "junk" DNA are thought to have no functional significance [3, 4]. Based on large scale studies of human and other eukaryotic genomes it is estimated that about 98 % of the transcriptional output of their genomes is RNA that does not encode protein implying that the genomes are gorged with either inept RNA transcripts or with ncRNA transcripts that exhibit unanticipated functions in eukaryotic biology. However, recent development of new technologies in molecular biology and human genetics such as genome tiling [4,5], microarrays, and next generation RNAsequencing (RNA-Seq) [6,7] have enabled the discovery of different types of ncRNAs that do not code for protein product [8-10]. Even though ncRNAs do not encode proteins, they play pivotal roles in the complex networks that are necessary to regulate cellular functions via transcriptional and translational regulation of protein coding genes that are crucial to normal development and physiology, and to disease [11]. Moreover, many of the ncRNAs are highly conserved and susceptible to epigenetic and genetic defects that affect normal development and disease process significantly [12-15].

There are copious non-coding transcripts that participate principally in regulating cellular protein synthesis, which are grouped into different classes based on their size, function and association with transcription start site [1, 12, 16-18]. According to their size, ncRNAs are categorized into: small ncRNAs, 20 to 200 nucleotides long, which includes microRNAs

© 2013 Ranganna et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

(miRNAs), PIWI-interacting RNAs (piRNAs) and small nucleolar RNAs (snoRNAs); long ncRNAs (lncRNAs) that are longer than 200 nucleotides; and macro ncRNAs, longer than 200 nucleotides that can reach 100 kilobases (kb) longer without being processed into small ncRNAs [1,7,12,18]. Based on where they are derived from within the genome, lncRNAs can be distinguished from each other. There are intronic lncRNAs (transcribed between exons of genes), intergenic lncRNAs (transcribed from the space between two genes) and lncRNAs that are derived from the regions that overlap both exon and intron of a coding gene. Furthermore, each of these ncRNAs may also be in the sense or in the antisense direction. According to functional significance, ncRNAs can be divided into: (1) housekeeping ncRNAs and (2) regulatory ncRNAs. Housekeeping ncRNAs include constitutively expressed ncRNAs that are crucial for the normal function and cellular viability, which include transfer RNAs, ribosomal RNAs, small nuclear RNAs, and snoRNAs [18]. On the contrary, regulatory ncRNAs or riboregulators include ncRNAs such as miRNAs and lncRNAs that are expressed in response to external signals, during different cellular states such as cellular differentiation or at certain stages of development, influencing the expression of other genes at transcription and transla‐ tional levels [1, 7, 12, 18]. Regarding ncRNAs that are associated with transcription start sites of genes, there are different classes of ncRNAs such as promoter-associated small RNAs (PASRs) [16], transcription start site-associated RNAs (TSSa-RNAs) [19], promoter upstream transcripts (PROMPTs) [20] and transcription initiation RNAs (tiRNAs) [21]. Even though their functional roles are poorly delineated, perhaps they have a regulatory role in transcription.

local blood pressure to facilitate distribution of oxygenated blood to different parts of the body. In adult vessels, VSMC proliferate at very low rate; display reduced synthetic activity; and express a unique compilation of proteins that is characteristic of contractile phenotype such as contractile proteins, ion channels, and signaling molecules. Yet, they still maintain remarkable plasticity and retain the ability to undergo extreme and reversible changes in phenotype in response to their local environmental signals, especially during vascular development, and in response to vascular injury as a key mechanism in wound healing. It is recognized vascular injury provoked by various atherogenic insults such as mechanical, chemical and immuno‐ logical injuries triggered by different disease risk factors promote VSMC activation, migration and proliferation, which are precursors to the development of atherosclerosis and neointimal hyperplasia [34, 35]. VSMC also undergo phenotypic modification from contractile to prolif‐ erative or synthetic phenotype in conjunction with vessel remodeling by altering the cell number and composition of vessel wall as the primary pathophysiological mechanism in different clinical pathologies such as postangioplasty restenosis, in-stent restenosis, and vein bypass graft failure and transplant vasculopathy [34-37]. However, the molecular mechanisms

MicroRNAome of Vascular Smooth Muscle Cells: Potential for MicroRNA-Based Vascular Therapies

http://dx.doi.org/10.5772/54636

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During the last few years there is an upsurge in ncRNA research specifically pertaining to a novel class of small miRNAs because of their role in various biological functions. In a variety of eukaryotic organisms miRNAs have been demonstrated to play key roles in various cellular processes including proliferation, differentiation, and apoptosis [38-40], which are central to normal development and physiology, and pathogenesis of diseases. As such, dysregulation of miRNAs has been linked to different diseases, including different cancers, neurological, cardiovascular and other diseases [22, 25-32]. Because of their effects on cellular processes as gene expression regulators, impairment of miRNAs as evidenced in many cancers, suggest involvement of miRNAs in the phenotypic modulation of VSMC both in normal and disease states. Here we briefly describe miRNAs, their biogenesis and mechanism of action and then summarize the recent progress in the functional significance of miRNAs in VSMC phenotypic

miRNAs are endogenous, well conserved, small ncRNAs, usually 20 to 26 nucleotides, that mediate posttranscriptional gene silencing by complimentary binding to the 3'-untranslated region (3'-UTR) of their target mRNA, leading to direct target mRNA degradation or transla‐ tional repression, a key phenomenon for controlling gene expression in a tissue- and devel‐ opment-specific manner [1, 38-40]. They were first detected in Caenorhabditis elegans as regulators of development in 1993 [41] and since then they have been found in many species of plants and animals. There are several differences between plants and eukaryotic mRNAs. In plants, transcriptional repressions require a perfect or near-perfect target match, whereas mismatched target can cause gene silencing at the translational level in eukaryotes. In eukar‐ yotes, miRNA complementarity typically includes the 5' bases 2-7 of the miRNAs, which is referred as miRNA "seed" region, Furthermore, one miRNA can target many different sites

involved in VSMC phenotypic control are still vague.

modulation and response to injury.

**3. miRNAs**

Among the ncRNAs, the most widely studied and comparatively well delineated regarding their functional relevance to normal development and physiology, and to pathogenesis of disease are, small microRNAs [1, 12, 22-25]. miRNA deficiencies or surpluses have been correlated with diverse clinically important diseases including various types of cancers, neurological diseases, metabolic diseases, cardiovascular diseases, and many others [22, 25-32]. Here, we provide an overview of the current knowledge of miRNAs that participate in the regulation of vascular smooth muscle cells (VSMC) phenotypic modulation and present the potential opportunities for miRNA-based therapeutic and diagnostic approaches for vascular proliferative diseases due to atherosclerosis and restenosis. Finally, we briefly describe our preliminary unpublished data on miRNA expression profile of VSMC in response to butyrate, a histone deacetylase (HDAC) inhibitor.
