Abstract

The short noncoding RNAs, known as microRNAs, are of undisputed importance in cellular signaling during differentiation and development, and during adaptive and maladaptive responses of adult tissues, including those that comprise the heart. Cardiac microRNAs are regulated by hemodynamic overload resulting from exercise or hypertension, in the response of surviving myocardium to myocardial infarction, and in response to environmental or systemic disruptions to homeostasis, such as those arising from diabetes. A large body of work has explored microRNA responses in both physiological and pathological contexts but there is still much to learn about their integrated actions on individual mRNAs and signaling pathways. This review will highlight key studies of microRNA regulation in cardiac stress and suggest possible approaches for more precise identification of microRNA targets, with a view to exploiting the resulting data for therapeutic purposes.

Highlights

  • Cells need to respond to changes in their external environment to ensure continued optimum function and survival

  • While CLASH was initially described in HEK293 cells overexpressing epitope-tagged Ago, the presence of chimeric reads corresponding to microRNA-messenger RNA (mRNA) ligation has been reported from human pancreatic islet cells subjected to Ago2 HITS-CLIP [62], suggesting that this approach will be useful in vivo

  • In a similar manner to the direct and indirect data on microRNA-mRNA interactions captured by RNA-induced silencing complexes (RISCs) RNA assessment vs measurement of global mRNA, the ultimate effects on mRNA translation can be captured by a direct method or less direct methods

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Summary

Introduction

Cells need to respond to changes in their external environment to ensure continued optimum function and survival. Prize-winning work on RNA interference by injected dsRNAs in C. elegans [1] Like their mRNA cousins, the production of microRNAs is responsive to cues from the external environment and other cellular signals; microRNAs arise from introns spliced out of pre-mRNAs or via RNA polymerase. The ability of microRNAs to engender large-scale changes in cellular behavior is the basis of both their potential and their peril, and suggests that a detailed understanding of which mRNAs they target, and how this may vary with context, is needed to fully understand the biology of these noncoding RNAs and to enable developing microRNA-based therapeutic strategies to be properly deployed. The experimental and analytic approaches outlined below may be valuable not just in studies and possible therapeutic uses of microRNAs in the heart, and in a wide variety of microRNA-based investigations

A ‘Systems’ Approach is Key to Understanding MicroRNA Signaling
Which Altered MicroRNAs may be of the Most Biological Significance?
Challenges Faced by MicroRNA Target Prediction Algorithms
Quantifying MicroRNA-Dependent Regulation of mRNAs
Assays for Altered Translation of mRNAs
Assessing microRNAs not Altered in the Stressed Heart
Contextual Interpretation of Direct MicroRNA-mRNA Interaction Data
MicroRNA Therapeutics for Stress Relief?
Conclusions
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