MicroRNA Regulation and Effects in Cardiac Hypertrophy

Cardiac disease resulting from hypertension (a poorly adaptive enlargement, or hypertrophy of the heart) is highly prevalent in the Western world and can prove difficult to detect until a progression to overt heart failure is evident. Exercise also makes demands on the heart to increase its output and causes superficially similar cardiac enlargement, but in this case the changes are beneficial. There is considerable interest in better understanding the difference between these forms of hypertrophy and limiting the damage that accumulates due to chronic hypertension, or the poor adaptation of surviving cardiomyocytes to the increased work demanded of them after myocardial infarction. Among many signaling mechanisms used in mammalian cells, the microRNA (miR) family of noncoding RNAs act at the post-transcriptional level to inhibit coding mRNA translation and are well positioned to serve as mediators of chronic stress responses. We hypothesize that individual miRs regulate beneficial and deleterious pathways of adaptation in the face of long-term alterations in cellular environment, such as those evident in physiological and pathological forms of cardiac hypertrophy, and that knowledge of their component actions and quantitative contributions to phenotypes will permit targeted pharmacologic manipulation to improve disease outcomes. The obstacles that stand in the way of achieving this knowledge are twofold; establishing which mRNAs a particular miR will target in a given cellular context, and then defining which miR alterations in disease will meaningfully affect mRNA translation.

We are attempting a radical rethink of how these questions have been tackled previously, with two major aims: firstly, to elucidate how overall miR-dependent gene regulation affects pathological and physiological cardiac hypertrophy, using a ‘top-down’, system-wide view of how dynamic changes in multiple, individual miRs and mRNAs are integrated to affect the response of the heart to stress. Unbiased, quantitative, ‘next-generation’ RNA expression analyses will be employed to study miRs, global mRNAs, mRNAs targeted and suppressed by miRs in the cellular RNA-induced silencing complex (RISC), and the extent to which mRNAs undergo ribosomal translation as a consequence.

Our second aim is to build a predictive network of individual miR-mRNA interactions during cardiac hypertrophy; a ‘bottom-up’, highly mechanistic approachdesigned to reveal and then test in vivo which manipulations of this complex cellular circuitry might promote adaptive ‘physiological’ responses while minimizing maladaptive ‘pathological’ behavior. Using novel informatic procedures to deconvolute experimental observations, the individual miR-mRNA pairs involved in cardiac stress responses will be defined; validation and recapitulation of their actions will be performed in vitro, showing how complex responses may be built from the ground up; and the resulting miRs predicted from such a ‘rational design’ approach to best shape beneficial and deleterious aspects of the cardiac hypertrophy phenotype will be tested in vivo.

These studies should make a significant contribution to understanding pathological cardiac hypertrophy and its progression to heart failure, but open the doors widely to applying a similar combination of ‘system-wide’ and ‘reductionist’ methodologies in order to understand how integrated miR actions contribute to health and disease in other contexts.

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