Critical Review miRNAs in Cardiac Disease: Sitting Duck or Moving Target? Carly J. Hynes, Jennifer L. Clancy, and Thomas Preiss Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT, Australia Summary Emerging findings indicate that cells can produce both micro (mi)RNAs and their messenger (m)RNA targets in multiple processing variants in a tissue- and developmental stage-selec- tive manner. Specifically, we find that cells accumulate a greater range of functional miRNAs than hitherto expected, whereas mRNAs with alternative 3 0 untranslated regions that include varying numbers of miRNA target sites are also seen to be common. This has important implications for both our understanding of miRNA function in a given biological context and the design of successful strategies for experimental or ther- apeutic intervention. In this review, we relate these new phenomena to miRNAs in the heart, where they are known to play critical roles during normal function as well as in cardiac disease. Ó 2012 IUBMB IUBMB Life, 64(11): 872–878, 2012 Keywords cardiac disease; miRNA biogenesis; miRNA-target inter- action; 3 0 untranslated region; mRNA 3 0 end cleavage; polyadenylation. INTRODUCTION micro (mi)RNAs are 22 nucleotide (nt) long regulatory RNAs derived from larger hairpin-containing precursors that guide miRNA-induced silencing complexes (miRISC) to par- tially complementary target sites within the 3 0 untranslated region (3 0 UTR) of the messenger (m)RNAs, attenuating their expression (1, 2). Their sheer number and ability to target large sections of cellular transcriptomes (3) illustrates their impor- tance to gene regulation and they have been found to affect most physiological and pathophysiological processes examined thus far. Unsurprisingly then, miRNAs are not only intimately involved in cardiovascular development and homeostasis, but miRNA dysregulation also is common in cardiac pathologies. In several cases, it was further shown that manipulating levels of specific miRNAs in animal models either exacerbated a given cardiac pathology or protected against it (4–8). Given that car- diovascular disease is a major human health problem, these findings have sparked multiple efforts to develop miRNA-based therapeutics to tackle pathological cardiac remodeling and dys- function in different cardiac cell types (9). Very recently, the presence of circulating miRNA in body fluids has also raised the possibility of their use as a diagnostic tool (10). The rich lit- erature-linking miRNAs to heart health and disease, as well as detailing their therapeutic promise has been expertly reviewed elsewhere (11–14). Research in many different settings has further produced detailed descriptions of the biogenesis of miRNA and their mechanism of action (reviewed in refs. 15, 16). These insights from basic miRNA biology are also being translated into the medical research arena. Of particular note, it is emerging that disease-relevant changes to miRNA activity may occur for sev- eral different reasons (17). First, mutations in miRNAs or target site sequences can alter functional interactions. Second, the lev- els of a given miRNA can be affected by altered rates of tran- scription and processing of its precursor, as well as through reg- ulation of miRNA stability. Third, variability in processing of a hairpin precursor can give rise to multiple miRNA variants, potentially with distinct targeting properties. Fourth, regulated changes to mRNA 3 0 UTR formation, by either inclusion or exclusion of target sites, can subject a given mRNA to, or with- draw it from, the regulatory influence of miRNAs. We focus here on the potential of the latter two phenomena to contribute to the intricacies of cardiac gene regulation as well as its patho- logical dysregulation. miRNA BIOGENESIS AND TARGETING About half of the miRNA loci in the human genome are intergenic and, akin to the situation of protein-coding genes, are Address correspondence to: Thomas Preiss or Jennifer Clancy, Ge- nome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 0200, Australia. Tel.: 161-2-6125-9690. Fax: 161-2-6125-2499. E- mail: thomas.preiss@ anu.edu.au or jennifer.clancy@anu.edu.au Received 31 July 2012; accepted 4 August 2012 ISSN 1521-6543 print/ISSN 1521-6551 online DOI: 10.1002/iub.1082 IUBMB Life, 64(11): 872–878, November 2012