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Review
. 2019 Jan:112:24-30.
doi: 10.1016/j.vph.2018.11.006. Epub 2018 Nov 29.

The function of miR-143, miR-145 and the MiR-143 host gene in cardiovascular development and disease

Francesca Vacante  1 , Laura Denby  1 , Judith C Sluimer  2 , Andrew H Baker  3
Affiliations
Review

The function of miR-143, miR-145 and the MiR-143 host gene in cardiovascular development and disease

Francesca Vacante et al. Vascul Pharmacol. 2019 Jan.

Abstract

Noncoding RNAs (long noncoding RNAs and small RNAs) are emerging as critical modulators of phenotypic changes associated with physiological and pathological contexts in a variety of cardiovascular diseases (CVDs). Although it has been well established that hereditable genetic alterations and exposure to risk factors are crucial in the development of CVDs, other critical regulators of cell function impact on disease processes. Here we discuss noncoding RNAs have only recently been identified as key players involved in the progression of disease. In particular, we discuss micro RNA (miR)-143/145 since they represent one of the most characterised microRNA clusters regulating smooth muscle cell (SMC) differentiation and phenotypic switch in response to vascular injury and remodelling. MiR143HG is a well conserved long noncoding RNA (lncRNA), which is the host gene for miR-143/145 and recently implicated in cardiac specification during heart development. Although the lncRNA-miRNA interactions have not been completely characterised, their crosstalk is now beginning to emerge and likely requires further research focus. In this review we give an overview of the biology of the genomic axis that is miR-143/145 and MiR143HG, focusing on their important functional role(s) in the cardiovascular system.

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Graphical abstract
Fig. 1
Fig. 1
Long noncoding RNA function. In the nucleus, lncRNAs can modulate gene expression by enhancing or repressing the transcription of specific genomic loci by recruiting chromatin modifying complexes or inhibiting the binding of transcriptional factors to their DNA targets [39]. They can also modulate the splicing process by inducing or inhibiting the abundance of specific transcripts [14]. In the cytoplasm they can modulate gene expression at post-transcriptional level, interacting with proteins or other ncRNAs (microRNAs and mRNAs). Many lncRNA seem to act as scaffold for the assembling of proteins involved in same molecular networks [40]. Some of them can also regulate the processing of their mRNA including translation and degradation [41]. LncRNA can act as molecular sponges for microRNAs thus limiting their capability to bind their targets. LncRNA can also encode short functional peptides called (micropeptides) [42]. Recentely, lncRNA have also been described as important players of cell-cell communication being secreted in the extracellular environment by extracellular vesicles [43].
Fig. 2
Fig. 2
Regulatory networks controlled by miR-143/145 in cardiovascular development and disease in vSMCs. Schematic illustration of the main pathways regulated by miR-143/145 in vSMCs. During development, miR-143/145 show high expression levels in the myocardium of mouse embryo (E7-E9). In late cardiogenesis, expression mainly correlates with the ventricles and atria (E15). The expression pattern is then inverted post-natally, where miR-143/145 is expressed only in the aorta and pulmonary arteries. In physiological conditions in adult mouse, the vascular-specific microRNA cluster controls the transcription of contractility and differentiation genes typical of a SMC signature (α-SMA, Calponin, Mhy11). Particularly, the transcriptional regulation of vSMC contractile phenotype involves binding of SRF/Myocd (Serum Responsive Factor/Myocardin) to the CArG box located on the promoter of contractility genes, which in turn induce the miR-143/145 expression. Importantly, miR-143/145 is also implicated in the regulation of the vSMCs phenotypic switch in vascular disease. Particularly, miR-143/145 was found dysregulated in response to vascular injury, such as hypoxia, stretch, shear stress, growth factors, pro-inflammatory cytokines, inducing genes regulating vSMC proliferation, migration and plasticity [12].
Fig. 3
Fig. 3
Schematic representation of human MiR143HG (Chr5 q32) and mouse (Chr18 E1) splice variants and pre-miRNA 143/145. The MiR143HG locus encodes for twelve lncRNA isoforms in human and two in mouse.
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