Advances in Genetics miR-143 and miR-145 Molecular Keys to Switch the Phenotype of Vascular Smooth Muscle Cells

Vascular smooth muscle cells (VSMCs) are able to perform both contractile and synthetic functions, which are associated with changes in morphology, proliferation, and migration rates and are characterized by the specific expression of different marker proteins. Under normal physiological conditions, VSMC rarely proliferate in adult tissues, but undergo major phenotypic changes from the contractile to the synthetic in response to environmental cues, a phenomenon known as switching, or phenotypic modulation.1,2 Phenotypic switching is accompanied by production of abundant cytokines, extracellular matrix, and an increased rate of proliferation and migration. Therefore, the transition of VSMCs from a differentiated phenotype to a dedifferentiated state plays a critical role in the pathogenesis of cardiovascular diseases such as hypertension, vascular injury, and arteriosclerosis.2,3 However, the molecular mechanisms involved in phenotypic switching remain elusive. The last decade has witnessed an exciting discovery that led to a revolution in our understanding of the extensive regulatory gene expression networks modulated by small, untranslated RNAs, microRNAs (miRNAs).4 miRNAs comprise a novel class of endogenous, small RNAs of 20 to 25 nucleotides. Although the mature miRNA is very small, it is derived from a transcriptional product of a few hundred to a few thousand nucleotides. This process of maturation is known as miRNA biogenesis, extensively reviewed by Kim.5 Biogenesis of miR-143 and miR-145 is pictorially presented in Figure 1. Functionally, miRNAs are noncoding RNAs that negatively regulate gene expression. In the current, generally accepted model, they act mostly by inducing an inhibition of the translation of their target mRNAs, and, in a minority of cases, via their degradation.6,7 Very recently, however, Bartel’s team challenged this view by showing that, in a vast majority of cases, mammalian microRNAs act by destabilizing their target mRNAs and decreasing their levels.8 They function as posttranscriptional regulators of mRNA expression by binding to the 3 UTR and repressing translation of the target gene.6,7 Note, however, that a few studies have described that some miRNAs bind the coding region or 5 UTR of respective target mRNAs.9–14 One single miRNA is able to regulate the expression of multiple genes because it is able to bind to its mRNA targets as either a perfect or imperfect complement.6,7 Thus, 1 miRNA can regulate the expression of multiple target genes. Similarly, 1 mRNA can be regulated by several miRNAs. It is speculated that the human genome may encode 1000 miRNAs15 that are abundant in many human cell types. Thus, the process of regulation of mRNA expression by miRNAs is complex, and explains that these small RNAs may target about 30% to 60% of the mammalian genes.16 Several miRNAs, including miR-21, miR-221, miR-222, miR-143, and miR-145, have a demonstrated role in VSMC differentiation. miR-21 negatively regulates programmed cell death 4 (PDCD4),17 promoting VSMC differentiation, whereas upregulation of miR-221 and miR-222 promotes VSMC proliferation by targeting the negative regulators of the cell cycle, p27 and p57.18,19 Several recent studies have demonstrated the critical role of miR-143 and miR-145 in VSMC phenotype switching.1,20–26 In this review, we specifically focus on the current, state-of-the-art information on miR-143 and miR-145 (henceforth these 2 miRNAs together will be designated as miR-143/145) and their involvement in phenotypic modulation of VSMCs and cardiovascular diseases. Further information about other miRNAs associated with VSMCs can be found elsewhere.27–33