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Are microRNAs opening up a new world of regulation?

The study by Bhattachariya et al. (2015) published in this issue of Acta Physiologica attracted my attention because of two reasons. On the one hand, the data of this study specifically propose that particular microRNAs, miR-143 and miR-145, play an important role for stretch-induced contractile differentiation and calcium homoeostasis in the portal vein. On the other hand, the data of this study also provide experimental evidence for a more general hypothesis stating that so-called organizational programmes may exist. These ‘organizational programs’ act at a level above the well-known signalling pathways to enable the flexible recruitment and fine-tuning of these signalling pathways into signalling networks for distinct functional responses. This emerging but almost untested concept was implied by a number of recent experimental studies and has been discussed lately by Lidington et al. (2013). The contribution to this concept explains my special interest in the study by Bhattachariya and colleagues and prompted me to focus in this editorial on the idea that microRNAs may serve as higher level ‘organizational programs’. What are the special features of microRNAs? In recent years, growing evidence has been accumulated demonstrating an important functional role of a cluster of regulatory molecules, microRNAs (miRs). miRs are a class of evolutionarily conserved short singlestranded non-coding RNAs (~22 nucleotides long) complementary to sequences in target mRNAs that negatively regulate gene expression by degrading or suppressing translation of target mRNAs. They have been shown to modulate various biological functions in animals, plants and unicellular eukaryotes. miRs were found to play crucial roles in many important biological processes such as cell proliferation, differentiation, growth, apoptosis, stress response, angiogenesis and tumorigenesis, in particular in the cardiovascular system. Moreover, miRs contribute to the initiation and progression of cardiovascular disease. Thus, the better understanding of the role of miRs in the cardiovascular system under physiological and pathophysiological conditions together with the increasing availability of miR mimics and miR inhibitors has led to the suggestion to use miRs as new diagnostic and prognostic markers as well as therapeutic targets in cardiovascular disease (Liu et al. 2011, McDonald et al. 2012, Figueira et al. 2014, Olson 2014, Maegdefessel et al. 2015, Wronska et al. 2015). The biogenesis of miRs is well known (for an overview see, for example, Figueira et al. 2014, Wronska et al. 2015). Briefly, several steps are required to produce miRs: (i) RNA polymerase II transcribes the miR gene, located in introns, exons and intergenic regions, yielding long pri-miRs; (ii) RNAse III (Drosha) in the canonical pathway and the spliceosome in the noncanonical pathway process pri-miRs to hairpin-like pre-miRs; (iii) exportin-5 exports pre-miRs into the cytosol; and (iv) RNAse III (Dicer) processes pre-miRs to mature miRs (miR-miR* duplexes). A number of miRs are located together in clusters. Thus, they are expressed together. The effector mechanism of miRs also consists of several steps: (i) formation together with Argonaute family proteins of RNA-induced silencing complexes (RISC); (ii) direction of RISC to the target mRNAs, a process guided by complementary sequences in the 30untranslated region of the target gene; and (iiia) degradation of mRNA in the case of high complementarity between the miR and the target mRNA or (iiib) repression of translation in the case of complementarity limited to the seed sequence (nucleotides 2–8 in the 50-region of a particular miR; miRs with the same seed sequence belong to one miR family). According to the mechanism described, miRs negatively regulate gene expression. However, some miRs have been shown to stimulate protein synthesis in the ribosome, therefore promoting gene expression. What does the new concept stating the existence of ‘organizational programs’ acting at a higher level above the well-known signalling pathways suggest (for a comprehensive discussion, see Lidington et al. 2013)? Of note, over the years an ever-growing number of signalling pathways, which often interact in complex networks, have been identified that regulate a multitude of processes in the circulatory system such as growth, differentiation, angiogenesis and contractility. Despite this large amount of information, many of these processes are still incompletely understood. This