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Cardiovascular Research Advance Access first published online on July 9, 2008
This version [Corrected Proof] published online on July 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn181
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Control of cardiac excitability by microRNAs

Baofeng Yang1,2,*, Yanjie Lu1,2 and Zhiguo Wang2,3,4,*

1 Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
2 Cardiovascular Research Institute, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
3 Research Center, Montreal Heart Institute, 5000 Belanger East, Montreal, Canada PQ H1T 1C8
4 Department of Medicine, University of Montreal, Montreal, Canada PQ H3C 3J7

* Corresponding authors. Tel: +86 451 8667 9473 (B.Y.) or Tel: +1 514 376 3330; Fax: +1 514 376 4452 (Z.W.) E-mail address: yangbf{at}ems.hrbmu.edu.cn (B.Y.) or wz.email{at}gmail.com (Z.W.)

Received 2 January 2008; revised 17 June 2008; accepted 19 June 2008

Time for primary review: 25 days


   Abstract
Top
 Abstract
1. Introduction
 2. miRNAs in the...
 3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
 5. Concluding remarks
 Funding
 References
 
Cardiovascular disease is the leading cause of morbidity and mortality in developed countries. The pathological process of the heart is associated with an altered expression profile of genes that are important for cardiac function. MicroRNAs (miRNAs) have recently emerged as one of the central players of gene expression regulation. The implications of miRNAs in the pathological process of the cardiovascular system have recently been recognized, and research on miRNAs in relation to cardiovascular disease has now become a most rapidly evolving field. In this review, we focus on miRNAs and control of cardiac excitability, aiming to provide a comprehensive overview on the available experimental data on regulation of cardiac conduction, repolarization, and automaticity by miRNAs. Aberrant expression of miRNAs in the diseased state of the heart and their arrhythmogenic or anti-arrhythmic potential will be discussed. Finally, the innovative miRNA-interference technologies developed lately for manipulating the action of miRNAs by interfering with their expression, stability, and function as new approaches for miRNA research and gene therapy will be introduced.

KEYWORDS miRNA; Arrhythmias; Cardiac excitability; Ion channels; Gene expression


   1. Introduction
Top
 Abstract
 1. Introduction
2. miRNAs in the...
 3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
 5. Concluding remarks
 Funding
 References
 
With the recent surge of research into microRNAs (miRNAs), this category of endogenous non-coding small ribonucleic acids has emerged as one of the central players of gene expression regulation, participating in many essential biological processes such as cell proliferation, differentiation, apoptosis, metabolism, stress, and so on.1,2 Functional or mature miRNAs are around 22-nucleotides in length. They are initially transcribed as long RNA precursors called primary miRNAs that require the RNase III enzyme Drosha in the nucleus to be trimmed into precursor miRNAs. The latter, characterized by a stem loop or hairpin structure of 70–100 nt, is exported by the nuclear export factor exportin-5 to the cytoplasm where they are subsequently cropped to become mature miRNAs of 21–26 nt long by another RNase III enzyme Dicer.3–7

Mature miRNAs can interact with Argonaute to form the RNA-induced silencing complex (RISC) and then guide the RISC to their target mRNAs by a partial base-paring mechanism, most favourably to the 3'-untranslated region (3'UTR). In order for an miRNA to elicit functional consequences, its 5'-end 7–8 nt must have exact complementarity to the target mRNA, the so-called ‘seed’ region, and partial complementarity to the rest of its sequence.8–12 An miRNA can either inhibit translation or induce degradation of its target mRNA or both, depending on the following factors: (i) the overall degree of complementarity of the binding site, (ii) the number of binding sites, and (iii) the accessibility of the binding sites (as determined by the free energy states). The greater the complementarity of the accessible binding sites, the more likely an miRNA degrades its targeted mRNA. Those miRNAs that display imperfect sequence complementarities with target mRNAs primarily result in translational inhibition.10–14 With better complementarity to the accessible binding sites, an miRNA could more likely degrade its targeted mRNA, and those miRNAs that display imperfect sequence complementarities with target mRNAs primarily result in translational inhibition. Greater action may be elicited by an miRNA if it has more than one accessible binding site in its targeted miRNA, owing to the potential cooperative miRNA–mRNA interactions from different sites. A recent study demonstrated, however, that miRNAs can also act to enhance translation when AU-rich elements and miRNA target sites coexist at proximity in the target mRNA and when the cells are in the state of cell-cycle arrest.15

MiRNAs are abundant RNA species, constituting >3% of the human genome, and are predicted to regulate ~30% of the protein-coding genes.16,17 Although the role of miRNAs in oncogenesis and cardiac development has been appreciated over the past few years, the involvement of miRNAs in the pathological process of the cardiovascular system has only been recognized very recently. It is now clear that in addition to their role in cardiac development,18–25 miRNAs are also critically involved in the pathological process of adult hearts, including cardiac hypertrophy,26–32 heart failure,27,32 cardiomyopathy,33 angiogenesis,34 and arrhythmogenesis.35 For example, with respect to hypertrophy, multiple miRNAs, including the muscle-specific miRNAs miR-1, miR-133, and miR-208 and other miRNAs (miR-195, miR-21, and miR-18b), have been identified to participate in and can independently determine the pathological process. The research on miRNAs in relation to cardiovascular disease has now become a most rapidly evolving field. Several excellent review articles and editorial commentaries on these subjects have been published lately.36–40 To avoid repeating the same information provided by these review articles, here we focus on miRNAs and control of cardiac excitability to give a comprehensive and analytical overview on the available experimental data on regulation of cardiac conduction, repolarization, and automaticity by miRNAs and their relation to arrhythmogenicity.


   2. miRNAs in the heart
Top
 Abstract
 1. Introduction
 2. miRNAs in the...
3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
 5. Concluding remarks
 Funding
 References
 
2.1 Expression profile of miRNAs in normal heart
The expression of miRNAs is dynamic, depredating on tissue/cell types, metabolic status, disease states, and so on. There is a certain expression profile of miRNAs in cardiac tissue, such as that found in any other tissue. This particular expression profile is often capped with ‘signature expression’, to indicate the tissue/cell-specific expression of an array of miRNAs. The miRNA expression profile in artery is different from that in heart. The most abundant miRNAs in cardiac muscles are miR-1, let-7, miR-133, miR-126–3p, miR-30c, and miR-26a.41 In coronary arterial smooth muscle cells, the most abundantly expressed miRNAs are miR-145, let-7, miR-125b, miR-125a, miR-23, and miR-143,34 although miR-1 and miR-133 are also expressed in coronary arterial smooth muscles. The differential tissue distributions of miRNAs suggest tissue-specific or even cell type-specific function of these molecules.

Among 500 mammalian miRNAs identified to date, miR-1, miR-133, and miR-208 are considered muscle-specific, being primarily expressed in cardiac and skeletal muscles.18–25 The miR-1 family consists of the miR-1 subfamily and miR-206, with the former consisting of two transcripts, miR-1-1 and miR-1-2, that possess an identical mature sequence but are encoded by distinct genes located on chromosomes 2 and 18, respectively. The miR-133 family comprised miR-133a-1, miR-133a-2, and miR-133b and is expressed from bicistronic units together with the miR-1 subfamily.19,20 The resulting mature products from the miR-133 family are either identical or have only 1 nt difference. miR-208 is encoded by an intron in the {alpha}-MHC gene.25 Cardiac muscle-specific expressions of miR-1 and miR-133 are controlled by serum responsive factor (SRF)/myocardin and of miR-208 are associated with an expression of {alpha}-MHC gene. A recent study, indeed, confirmed that >90% of the miR-1 transcripts were blocked in the SRF knockout hearts.42 In comparison, skeletal muscle-specific expressions of miR-1 and miR-133 are controlled by MyoD/MEF2.19,43 These data suggest that the tissue-specific expressions of miRNAs are largely determined by transcription factors.

2.2 Aberrant expression of miRNAs in diseased heart
The expression profile of miRNAs in a given tissue is also disease state-dependent. A particular pathological process is associated with the expression of a particular group of miRNAs. These signature patterns could aid in the diagnosis and prognosis of human disease, as evidenced by recent studies on cardiovascular disease and human cancer.

Myocardial ischaemia triggers a series of pathological remodelling processes of the heart with a manifestation of gene expression alterations. The aberrant gene expression can cause many malfunctions of the heart with impaired cardiac excitability. We found that miR-1 is overexpressed (~2.8-fold increase) in the myocardium of individuals with coronary artery disease relative to healthy hearts.35 To explore the mechanisms, we used a rat model of myocardial infarction induced by occlusion of the left anterior descending coronary artery for 12 h that corresponds to the peri-infarction period during which phase II ischaemic arrhythmias often occur, which represents a major challenge to our understanding and management of the disorder.44 We found a similar increase (~2.6 fold) in miR-1 expression in this animal model, which was accompanied by exacerbated arrhythmogenesis.35

The adult heart is susceptible to stress (such as haemodynamic alterations associated with myocardial infarction, hypertension, aortic stenosis, valvular dysfunction, and so on) by undergoing remodelling process, including electrical remodelling, and hypertrophic growth to adapt to altered workload and impaired cardiac function. The remodelling process can eventually lead to heart failure. The whole process is characterized by the reprogramming of cardiac gene expression and the reactivation of ‘fetal’ cardiac genes.45 To date, there have been seven published studies on the role of miRNAs and cardiac hypertrophy.26–32 The common finding of these studies is that an array of miRNAs is significantly altered in their expression, either up- or downregulated, and that single miRNAs can critically determine the progression of cardiac hypertrophy.36 Olson's group reported a study on miRNAs that were regulated during cardiac hypertrophy and heart failure.27 They found more than 12 miRNAs that are up- or downregulated in rat cardiac tissue from mice in response to transverse aortic constriction (TAC) or expression of activated calcineurin stimuli that induce pathological cardiac remodelling. The same group recently found that miR-208 is increased in its transcript level in cardiomyocyte hypertrophy.26 Abdellatif and coworkers28 reported an array of miRNAs that are differentially and temporally regulated during cardiac hypertrophy. They found that miR-1 was singularly downregulated as early as day 1, persisting through day 7, after TAC-induced hypertrophy in a mouse model. Their study also suggests that miRNA expression profiles at different time points after TAC are different, with an expression of more than 50 miRNAs progressively changing during the development of pressure overload cardiac hypertrophy. A study from Condorelli's group focuses on the role of miR-133 and miR-1 in cardiac hypertrophy with three murine models: TAC mice, transgenic mice with selective cardiac overexpression of a constitutively active mutant of the Akt kinase, and human tissues from patients with cardiac hypertrophy.29 They showed that cardiac hypertrophy in all three models resulted in reduced expression levels of both miR-133 and miR-1 in the left ventricle (LV). Cheng et al.30 identified 19 deregulated miRNAs in hypertrophic mouse hearts after aortic banding. Consistently, another independent group identified 17 miRNAs upregulated and 3 miRNAs downregulated in TAC mice and 7 upregulated and 4 downregulated in phenylephrine-induced hypertrophy of neonatal cardiomyocytes.30 A study directed to the human heart identified 67 significantly upregulated miRNAs and 43 significantly downregulated miRNAs in failing LVs vs. normal hearts.32 Interestingly, 86.6% of the miRNAs induced and 83.7% of the repressed miRNAs were regulated in the same direction in fetal and failing heart tissue when compared with healthy hearts, being consistent with the activation of ‘fetal’ cardiac genes in heart failure. In another study, Ikeda et al.33 measured expression of 428 miRNAs in human LV samples from patients of healthy control, ischaemic cardiomyopathy, dilated cardiomyopathy, or aortic stenosis and identified 43 miRNAs that were differentially expressed in at least one disease group. The most consistent changes reported by these studies using microarray are upregulation of miR-21 (six of six studies), miR-23a (four of six), miR-125b (five of six), and miR-214 (four of six) and down-regulation of miR-150 (five of six studies) and miR-30 (five of six) (see Figure 1 for further illustration).


Figure 1
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  		Figure 1 Diagram depicting the differential expression profiles of miRNAs in cardiac hypertrophy and myocardial infarction. The data for cardiac hypertrophy are taken from seven published studies,38,43–48 and those on myocardial infarction were from our previous study41 and our unpublished observations. The miRNAs above the horizontal line represent those that are upregulated and the miRNAs below the horizontal line represent those that are downregulated. The framed miRNAs indicate those that demonstrate opposite directions of changes between cardiac hypertrophy and myocardial infarction. The miRNAs listed away from the horizontal line for cardiac hypertrophy are those that better reproduced in their changes by different laboratories. For myocardial infarction, the miRNAs listed away from the horizontal line are those that demonstrate greater changes in their expression.

 
Also interesting to note is that some of the miRNAs demonstrated the opposite direction of changes in their expression between ischaemic myocardium and hypertrophic hearts. For example, miR-1, let-7, miR-181b, miR-29a, and miR-30a/e, which are upregulated in ischaemic myocardium, are downregulated in hypertrophy. Similarly, miR-208, miR-214, miR-320, and miR-351, which are downregulated in ischaemic myocardium, are upregulated in hypertrophy (Figure 1). This fact further reinforces the notion that different pathological conditions have different expression profiles.

An important point is that miRNAs that are modulated during heart disease may not be necessarily involved in the disease process. It is, therefore, required that after expression profiling, experiments need to be conducted to investigate the function of modulated miRNAs. When experimental approaches are not feasible for a particular case (for example, too many modulated miRNAs to test), bioinformatics analysis may help.


   3. miRNAs and cardiac excitability
Top
 Abstract
 1. Introduction
 2. miRNAs in the...
 3. miRNAs and cardiac...
4. miRNAs and arrhythmogenicity
 5. Concluding remarks
 Funding
 References
 
Cardiomyocytes are excitable cells that can generate and propagate excitations; excitability is a fundamental characteristic of these cells. Cardiac excitability is conferred by three basic elements: automaticity, cardiac conduction, and membrane repolarization. Automaticity is a measure of the ease of cells to generate excitations or spontaneous action potentials. Conduction refers to the propagation of excitation within a cell and between cells, and cardiac conduction velocity is determined by the rate of membrane depolarization and the intercellular conductance. The rate of membrane repolarization determines the length of action potential duration (APD) and effective refractory period (ERP), thereby the timeframe of availability to generate the next excitation in a cardiac cell. These three intrinsic properties are reflected by electrical activities in cardiac cells. The electrical activities of the heart are orchestrated by multiple categories of ion channels: the transmembrane proteins that control the movement of ions across the cytoplasmic membrane of cardiomyocytes. Sodium (Na+) channels determine the rate of membrane depolarization, and connexin43 (Cx43) is critical for ventricular gap junction communication, being responsible for excitation generation and inter-cell conductance of excitation, respectively. Calcium channels (L-type Ca2+) account for excitation–contraction coupling and contribute to pacemaker activities in the sinoatrial and atrioventricular nodal cells. Potassium (K+) channels govern the membrane potential and the rate of membrane repolarization. Pacemaker channels, which carry the non-selective cation currents, are critical in generating sinus rhythm and ectopic heart beats as well. Intricate interplays of all these ion channels maintain the normal heart rhythm. Channelopathies, or dysfunction of the ion channels, which may result from genetic alterations in ion channel genes or aberrant expression of these genes, can render electrical disturbances predisposing to cardiac arrhythmias.46

Intriguingly, in addition to the muscle-specific miRNAs, other miRNAs that are altered in their expression in ischaemic myocardium and hypertrophic hearts36 may also be able to regulate the expression of cardiac ion channel genes. According to our bioinformatics prediction, let-7f, miR-23a, miR-29a, miR-30, miR-124a, miR-125b, miR-150, miR-193, miR-214, miR-185, miR-494, miR-320, and miR-351 all have cardiac ion channel genes as their putative targets. For instance, miR-30 that is remarkably increased in its transcript level in myocardial infarction and decreased in cardiac hypertrophy36 could theoretically regulate several cardiac ion channel genes including GJA1 (encoding connexin 43), CACNB2 (dihydropyridine-sensitive L-type, calcium channel β2 subunit), and KCNJ3 (Kir3.1 or GIRK1, a subunit of ACh-sensitive K+ channel). miR-195, which was found to be among the most upregulated miRNAs in cardiac hypertrophy,27 is predicted to target SCN5A (encoding cardiac Na+ channel {alpha}-subunit), KCNJ2 (encoding Kir2.1, a pore-forming {alpha}-subunit of inward rectifier K+ channel), and KCNAB1 (β1-subunit of Shaker-type voltage-gated K+ channels).

3.1 Regulation of cardiac conduction
We have experimentally established GJA1 and KCNJ2 as target genes for miR-1 with luciferase reporter activity assay and western blot analysis.35 Forced expression of miR-1 in both ischaemic and healthy myocardium by in vivo gene transfer procedures represses the expression of GJA1 and KCNJ2, whereas the anti-miRNA antisense inhibitor oligonucleotides (AMO) reversed the effects of miR-1 when co-applied and enhanced the expression when applied alone, presumably by inhibiting the endogenous miR-1. Cx43 (the gene product of GJA1) is critical for inter-cell conductance,47–49 and Kir2.1 governs the cardiac membrane potential,50–52 both of which are important determinants of cardiac excitability. Repression of these proteins by miR-1 is expected to render slowing of cardiac conduction (see Figure 2 for further illustration).


Figure 2
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  		Figure 2 Schematic illustration of the proposed role of the muscle-specific miRNAs miR-1 and miR-133 in arrhythmogenesis. Dashed arrows, post-transcriptional repression; solid arrows, indicating the cause–effect relationships; Cx43, connexin-43; IK1, inward rectifier K+ current; IKr, rapid delayed rectifier K+ current; IKs, slow delayed rectifier K+ current; If, pacemaker non-selective cation current or funny current; Kir2.1, a pore-forming K+ channel {alpha}-subunit for IK1; HERG, a pore-forming K+ channel {alpha}-subunit for IKr; KCNQ1, a pore-forming K+ channel {alpha}-subunit for IKs; KCNE1, an auxiliary β-subunit for IKs; HCN2 and HCN4, {alpha}-subunits for If; APD, action potential duration; ERP, effective refractory period; EAD, early afterdepolarization; TA, triggered activities.

 
Zhao et al.22,53 determined in vivo miR-1-2 targets, including the cardiac transcription factor, Irx5, which represses KCND2, a potassium channel subunit (Kv4.2) responsible for transient outward K+ current (Ito) in rodents. Their study suggests that the combined loss of Irx5 and Irx4 disrupted mouse ventricular repolarization with a predisposition to arrhythmias. The increase in Irx5 and Irx4 protein levels in miR-1-2 mutants corresponded well with a decrease in the KCND2 expression. Clearly, loss-of-function of miR-1 and Dicer mutant embryos affect conductivity through K+ channels, which supports a central role for miR-1 for fine-tuning the regulation of cardiac electrophysiology in pathological and normal conditions.

3.2 Regulation of cardiac repolarization
Cardiac repolarization is determined by an intricate interplay and a delicate balance between inward and outward ion currents. The rate of repolarization importantly affects the likelihood of arrhythmogenesis, and regional dispersion of ventricular repolarization is a marker of arrhythmogenicity risk.54,55 The spatial heterogeneity of cardiac repolarization is largely due to diversity and varying densities of repolarizing K+ currents.56–58 Slowly activating delayed rectifier K+ current (IKs) along with its underlying channel proteins KCNQ1 (pore-forming {alpha}-subunit) and KCNE1 (auxiliary β-subunit) importantly affect cardiac APD and arrhythmogenesis through two mechanisms. First, IKs acts as a powerful repolarization reserve or safety factor to restrict excessive cardiac APD and QT prolongation caused by other factors. Removal of this safety factor facilitates LQTS.55 Secondly, the distribution of IKs in the heart follows important spatial patterns in at least four different axes: (i) transmural heterogeneity with epicardium (Epi)≥endocardium (Endo)>midmyocardium (Mid)56,59 and (ii) interventricular gradient with right ventricle (RV)>LV,60,61 transseptal gradient with RV septum>LV septum,62 and apex–base difference with apical area>basal area.63 These intrinsic spatial patterns of distribution are important in maintaining the sequential excitation of cardiac muscles, and disruption of the patterns and/or exaggeration of the regional heterogeneity can create substrates for arrhythmogenesis. We have experimentally established KCNQ1 and KCNE1, the long QT syndrome genes, as targets for repression by miR-133 and miR-1, respectively.64 More importantly, we found that the distribution of miR-133 and miR-1 transcripts within the heart is also spatially heterogeneous with the patterns corresponding to the spatial distribution of KCNQ1 and KCNE1 proteins and IKs. Specifically, the miR-133 level was found when base>apex and mid>epi, a pattern reciprocal to the regional distribution of KCNQ1 proteins. The same mechanisms can be applied to miR-1 and KCNE1; the characteristic regional distributions of miR-1, Base>Apex and Epi>Mid, can be one of the causal factors for the converse transmural and apical–basal gradients of KCNE1 protein levels. miR-1 and miR-133 do not show any chamber-dependent differences. It should be noted that in addition to miR-1 and miR-133, other factors, such as transcription factor stimulating protein-1, have been shown to regulate transcription of KCNQ1 and KCNE1 genes, which also contributes to the regional heterogeneity of IKs.56,64

We have previously found that the ether-a-go-go related gene (ERG), another long QT syndrome gene encoding a key K+ channel (IKr) in cardiac cells, is severely depressed in its expression at the protein level, but not at the mRNA level in alloxan-induced diabetes of rabbits.65 The reduced protein level of ERG is a causal factor for the abnormal QT prolongation in diabetic hearts. In an effort to understand the mechanisms underlying the disparate alteration of ERG protein and mRNA, we performed a study on expression regulation of ERG by miRNAs in a rabbit model of diabetes.66 We found a remarkable overexpression of miR-133 in diabetic hearts; in parallel, the expression of serum response factor (SRF), a transactivator of miR-133, was also found robustly increased. Delivery of exogenous miR-133 into the rabbit myocytes and cell lines produced post-transcriptional repression of ERG, thus downregulating ERG protein level without altering its transcript level. Correspondingly, forced expression of miR-133 also caused substantial depression of IKr, an effect abrogated by the miR-133 antisense inhibitor. Functional inhibition or gene silencing of SRF downregulated miR-133 expression and increased IKr density. Repression of ERG by miR-133 likely underlies the differential changes of ERG protein and transcript, thereby the depression of IKr in diabetic cardiomyopathy.

3.3 Regulation of cardiac automaticity
The pacemaker current If, carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in rhythmogenesis. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenicity under these conditions.67,68 We performed a study on the post-transcriptional regulation of HCN2 and HCN4 by miRNAs, experimentally establishing HCN2 mRNA as a target for repression by the muscle-specific miRNAs miR-1 and miR-133 and HCN4 as a target for miR-1 only.69 We further unravelled robust increases in HCN2/HCN4 transcripts and protein levels in a rat model of LV hypertrophy induced by aortic stenosis (narrowing of the abdominal aorta above the left renal artery) and in angiotensin II-induced neonatal cardiomyocyte hypertrophy.69 The upregulation of HCN2/HCN4 was accompanied by a reduction of miR-1/miR-133. Overexpression of miR-1/miR-133 by transfection prevented largely the overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. Our data indicate that miR-1/miR-133 acts to limit overexpression of HCN2/HCN4 at the protein level, and downregulation of miR-1/miR-133 underlies partially the abnormal enhancement of HCN2/HCN4 expression in hypertrophic hearts (Figure 2).


   4. miRNAs and arrhythmogenicity
Top
 Abstract
 1. Introduction
 2. miRNAs in the...
 3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
5. Concluding remarks
 Funding
 References
 
Cardiovascular diseases remain the major cause of mortality and morbidity in developed countries. Most of these deaths are sudden, occurring secondary to ventricular arrhythmias such as tachycardia/fibrillation (VT/VF).46,70 Arrhythmias are electrical disturbances that can result in irregular heart beating. The hypothesis of altered excitability suggests that for arrhythmias to arise, the normal matrix must be perturbed by arrhythmogenic substrates to produce a proarrhythmic matrical condition to permit rhythmic disturbances caused by impaired excitation conduction/propagation, enhanced automaticity, or abnormal repolarization. Cardiac ion channels are fundamental determinants of cardiac excitability. Abnormalities of these ion channels, channelopathies, can be attributed to mutations in the genes encoding the channel proteins, which can predispose to arrhythmias. In many cases, malfunction of ion channels can also be ascribed to abnormally altered expression. Our findings that miRNAs regulate expression of cardiac ion channels strongly indicate a possibility of these miRNAs to influence arrhythmogenicity. The published studies have indeed generated data in support of this notion.

One of the most deleterious alterations during myocardial infarction is the occurrence of ischaemic arrhythmias. We demonstrated that delivery of miR-1 into the myocardium by in vivo gene transfer approach induces arrhythmias in otherwise healthy normal hearts and promotes arrhythmias including VT and VF in a rat model of myocardial infarction.35 These effects were reversible when miR-1 was knocked down by its specific antisense (AMO). More strikingly, delivery of AMO alone significantly suppresses the spontaneous ischaemic arrhythmias, presumably by antagonizing the endogenous miR-1 that is upregulated during ischaemia. The arrhythmogenic action of miR-1 is likely mediated by its repression of GJA1/Cx43 and KCNJ2/Kir2.1. As a further evidence, we showed that co-injection of a small inhibitory RNA targeting either Cx43 or Kir2.1 with miR-1 AMO into the myocardium of ischaemic rat hearts induced significant arrhythmias, despite the downregulation of miR-1 by the co-applied AMO. We therefore proposed that myocardial infarction upregulates miR-1 expression via some unknown factors, which induces post-transcriptional repression of GJA1 and KCNJ2, resulting in conduction slowing leading to ischaemic arrhythmias (Figure 2).

Abnormal QT interval prolongation is a prominent electrical disorder and has been proposed to be a predictor of mortality in patients with diabetes mellitus, presumably because it is associated with an increased risk of sudden cardiac death consequent to lethal ventricular arrhythmias.71,72 ERG K+ channels play a critical role in governing cardiac APD, and impairment of ERG can cause substantial prolongation of APD favouring occurrence of early afterdepolarizations, being the major cause of the acquired long QT syndrome. Repression of ERG by miR-133 likely underlies depression of EAG function and contributes to repolarization, thereby slowing QT prolongation and the associated arrhythmias in diabetic hearts. In addition to ERG/IKr, we found that miR-133 also repressed KCNQ1/IKs.64 It is possible that effect of miR-133 also contributes to increased risk of arrhythmogenicity in diabetic hearts.

It should be noted that inhibition of ERG/IKr and KCNQ1/IKs by miR-133 could also be anti-arrhythmic under certain circumstances because the consequent prolongation of APD can lengthen ERP to reduce the likelihood of re-entrant types of arrhythmias (Figure 2). This notion merits detailed studies.

Repression of pacemaker channel genes HCN2 and HCN4 by miR-1 and miR-133 may confer their anti-arrhythmic capability. HCN2 is primarily expressed in ventricular myocytes where it can elicit ectopic heart beat leading to arrhythmias, whereas HCN4 is mainly distributed in the sinus nodal cells where it is critical for heart beat generation and heart rate regulation. The suppression of ectopic beat by suppressing HCN2 can antagonize arrhythmias, and reduction of heart rate by suppressing HCN4 can minimize myocardial injuries during ischaemia. We then can speculate that in myocardial infarction, increased miR-1 level is expected to decrease HCN2 and HCN4 expressions and to limit enhancement of automaticity and occurrence of the associated arrhythmias. In contrast, in hypertrophic hearts, expression of miR-1 and miR-133 is supposed to reduce. We have shown that this reduction contributes to the re-expression of HCN2/HCN4 and the enhanced automaticity.69 Under such conditions, arrhythmias arisen from ectopic beat may increase.

The loss of cardiomyocytes due to apoptosis or necrosis following myocardial infarction or in heart failure irreversibly damages the myocardium. Loss of myocytes, no matter due to apoptosis or necrosis, can stimulate generation of fibrosis to fill the gap between living myocytes. This procedure produces discontinuity and anisotropy of cardiac conduction and propagation, one of the determinants of arrhythmogenesis.73–77 One important form of cell death during myocardial infarction or heart failure is apoptosis, a programmed cell death.73 Our study showed that miR-1 and miR-133 produced opposing effects on apoptosis induced by oxidative stress in H9c2 rat ventricular cells, with miR-1 being proapoptotic and miR-133 being antiapoptotic,78 the former targeting the antiapoptotic molecules such as heat shock protein-60 (HSP60) and HSP70 and the latter targeting caspase-9. We therefore speculated that the proapoptotic action of miR-1 may also be a part of the mechanisms for its proarrhythmic effects. Nonetheless, detailed studies are absolutely required to test this notion.


   5. Concluding remarks
Top
 Abstract
 1. Introduction
 2. miRNAs in the...
 3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
 5. Concluding remarks
Funding
 References
 
The research results summarized earlier clearly indicate that miRNAs regulate the expression of multiple ion channels. The cardiac ion channel genes that have been experimentally confirmed to be targets of miR-1 or miR-133 include GJA1/Cx43/IJ,35 KCNJ2/Kir2.1/IK1,35 KCNH2/HERG/IKr,66 KCNQ1/KvLQT1/IKs,64 KCNE1/minK/IKs,64 and HCN2 and HCN4/f-channel/If69 (see Table 1 for more details). The fact that deregulated expression of miRNAs can alter the expression of cardiac ion channels revealed a novel insight into the molecular basis of cardiac excitability. The concept of channelopathies is not merely restricted to genetic disorders; instead, post-transcriptional repression of ion channels by miRNAs may underlie the fatal arrhythmias associated with certain cardiac conditions such as cardiac hypertrophy, heart failure, and myocardial ischaemia. Recognizing miRNAs as a novel mechanism for channelopathies provides the basis for new strategies of treatment, including tailored pharmacotherapy and gene therapy.


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  		Table 1 Cardiac ion channel genes as targets for post-transcriptional repression of miR-1 and miR-133

 
However, our current understanding of miRNAs as regulators of cardiac excitability remains, at best, rudimentary. The studies in the literature have been limited to the muscle-specific miRNAs miR-1/miR-133, although bioinformatics predict the potential of many other miRNAs to regulate expression of ion channel genes. Also noteworthy is that the known miRNAs may represent only a partial list of the total number of actually existing miRNAs in the human body. Thorough understanding of miRNA regulation of ion channels will not be achieved until all natural miRNAs have been identified.

Moreover, with the rapid evolving of the research field, more focused questions have arisen. miRNAs are aberrantly expressed in diseased hearts, but how does this happen? Particularly, the patterns of expression of miRNAs vary depending on the nature of the pathological process and some miRNAs changes in their expression in the opposite direction between myocardial infarction and cardiac hypertrophy. Are these characteristic alterations of miRNAs related to differential alterations of cardiac excitability under different conditions? A given ion channel gene might be regulated by multiple miRNAs, but how do these miRNAs interplay to fine-tune the expression of the gene.

Finally, the pathophysiological significance of miRNA regulation of cardiac excitability has just been scrutinized with a paucity of studies. It is pivotal that further mechanistic studies should be performed for a proper transition from ‘bench to beside’. Although promising, miRNAs as a potential novel target for anti-arrhythmic therapy due to their ability to regulate cardiac excitability remains elusive. Detailed investigation should help address the key questions with respect to the issue.


   Funding
Top
 Abstract
 1. Introduction
 2. miRNAs in the...
 3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
 5. Concluding remarks
 Funding
References
 
This work was supported in part by the Canadian Institute of Health Research, Fonds de la Recherche de l'Institut de Cardiologie de Montreal, awarded to Z.W., and by the National Basic Research Program of China (973 Program; 2007CB512000/2007CB512006) awarded to B.Y. Z.W. is a senior research scholar of the Fonds de Recherche en Sante de Quebec and a LongJiang Scholar Professor of Heilongjiang, China.


   Acknowledgements
 
The authors thank XiaoFan Yang for excellent technical support.

Conflict of interest: The authors declare no potential conflict of interest that might constitute an embarrassment to any of the authors.


   References
Top
 Abstract
 1. Introduction
 2. miRNAs in the...
 3. miRNAs and cardiac...
 4. miRNAs and arrhythmogenicity
 5. Concluding remarks
 Funding
 References
 

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