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Review
. 2008 Oct 24;103(9):919-28.
doi: 10.1161/CIRCRESAHA.108.183426.

Toward microRNA-based therapeutics for heart disease: the sense in antisense

Eva van Rooij  1 , William S Marshall, Eric N Olson
Affiliations
Review

Toward microRNA-based therapeutics for heart disease: the sense in antisense

Eva van Rooij et al. Circ Res. .

Abstract

MicroRNAs act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Because individual microRNAs often regulate the expression of multiple target genes with related functions, modulating the expression of a single microRNA can, in principle, influence an entire gene network and thereby modify complex disease phenotypes. Recent studies have identified signature expression patterns of microRNAs associated with pathological cardiac hypertrophy, heart failure, and myocardial infarction in humans and mouse models of heart disease. Gain- and loss-of-function studies in mice have revealed profound and unexpected functions for these microRNAs in numerous facets of cardiac biology, including the control of myocyte growth, contractility, fibrosis, and angiogenesis, providing glimpses of new regulatory mechanisms and potential therapeutic targets for heart disease. Especially intriguing is the discovery of a network of muscle-specific microRNAs embedded within myosin heavy chain genes, which control myosin expression and the response of the heart to stress and thyroid hormone signaling. Disease-inducing cardiac microRNAs can be persistently silenced in vivo through systemic delivery of antimiRs, allowing for the direct therapeutic modulation of disease mechanisms. Here, we summarize current knowledge of the roles of miRNAs in heart disease and consider the advantages and potential challenges of microRNA-based approaches compared to conventional drug-based therapies.

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Figures

Figure 1
Figure 1. miRNA function during heart disease
Cardiac remodeling involves numerous disease processes. It is becoming increasingly clear that miRNAs fulfill specific functions during this process. While miR-21, -133, -150, -195 and -214 influence cardiomyocyte hypertrophy, miR-1 and -133 have additionally been implicated in cardiac arrhythmogenesis. In addition miR-21 and miR-195 also appear to influence apoptosis. miRNA-208 influences cardiac contractility by regulating myosin content and by so doing secondarily influences hypertrophy and fibrosis. The process of cardiac fibrosis is regulated by miR-21 and -29, both of which are highly expressed in cardiac fibroblasts. Neoangiogenesis post-MI relies on miR-126.
Figure 2
Figure 2. RNAi based technologies to regulate miRNA function in vivo
A) miRNAs are generated from pre-miRNAs by Dicer, giving rise to a duplex containing the mature miRNA and a partially complementary strand, referred to as miRNA*. AntimiRs are single stranded, antisense oligonucleotides designed to inhibit miRNA function. The perfect sequence complementarity allows the antisense oligonucleotide to bind to the miRNA and interfere with miRNA function (indicated in red). Although the exact mechanism of action remains undefined, this approach has been proven to be efficacious in vivo in preventing repression by the miRNA. One class of antimiR, the antagomir, is conjugated to cholesterol to facilitate cellular uptake (1). Other approaches use the oligonucleotides employing the locked nucleic acid (LNA) phosphorothioate chemistry (2) or the widely employed 2′-O-methoxyethyl phosphorothioate (MOE) modification (3). miR mimics are short double stranded oligonucleotides in which one strand is identical to the mature miRNA sequence (guide strand) and a complimentary or partially complementary stand is complexed with the mature miRNA sequence (passenger strand). The double stranded structure is required for efficient recognition and loading of the guide strand into the RNA Induced Silencing Complex (RISC) complex, after which it can function like the endogenous miRNA to increase the level of the miRNA of interest and more potently block targeted gene expression (indicated in green). B) In addition to tools available to directly target a miRNA or reduce miRNA levels, there are several potential approaches to target a miRNA pathway. One way of interfering with miRNA function is by scavenging away the miRNA and thereby preventing it from binding its mRNA targets, called sponging. In this technique, a series of either perfectly or imperfectly paired binding sites for a specific miRNA are introduced into an expression cassette in the 3′ untranslated region of a reporter gene. The multiplexed binding sites serve as competitive inhibitors and occupy the specific native miRNA-programmed RISC complexes in the cell. The association of a miRNA with a specific mRNA target can also be perturbed using an occupier, an oligonucleotide with perfect complementarity to the miRNA target sequence in the 3′ UTR of the mRNA, which thereby masks the binding site and prevents association with the miRNA. A theoretical advantage of this approach is its specificity. Since a miRNA has multiple targets, directly inhibiting a miRNA will influence all downstream targets, which may increase the probability of off-targets effects, while target occupation can modulate the interaction of a miRNA with one specific target. A third approach to inhibit miR function involves so-called erasers, in which expression of a tandem repeat of a perfect complementary sequence of the target miR inhibits endogenous miRNA. Although ‘sponging’, ‘masking’ and ‘erasing’ provide interesting opportunities to interfere with miRNA function, to date no studies have been published that prove their in vivo efficacy.
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