Critical Review

Role of MicroRNAs in Cardiac Hypertrophy and Heart Failure

Nan Wang1,2, Zhen Zhou1,2, Xinghua Liao1,2 and Tongcun Zhang1,21Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin, China2College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China

Summary

MicroRNAs (miRNAs) are a class of endogenous, highly con-served, small noncoding RNAs that regulate gene expressionpost-transcriptionally. Recent studies have demonstrated thatmiRNAs are aberrantly expressed in the cardiovascular system.The implications of miRNAs in cardiovascular disease haverecently been recognized, representing the most rapidly evolv-ing research field. Gain- and loss-of-function studies in micemodels have identified distinct roles for specific miRNAs duringcardiac hypertrophy, heart failing, and myocardial infarction.In the present article, the currently relevant findings on therole of miRNAs in cardiac hypertrophy and heart failure willbe summarized and the target genes and signaling pathwayslinking these miRNAs will be discussed. Furthermore, we focuson the use of miRNA mimics and antagonists (antagomirs) astools for disease therapy in the cardiovascular system in thefuture. Taken together, the recent studies showed that miRNAsare key regulators of gene expression in cardiovascular biologyand suggested the potential importance of miRNAs as diagnos-tic markers and therapeutic targets for cardiovasculardisease. � 2009 IUBMB

IUBMB Life, 61(6): 566–571, 2009

Keywords microRNAs; cardiac hypertrophy; heart failure; cardiovas-

cular disease; antagomirs.

INTRODUCTION

MicroRNAs (miRNAs) are endogenous, single-stranded,

small, �22-nucleotide (nt) noncoding RNAs that regulate target

gene. The first miRNA assigned to a specific function was lin-

4, which targets lin-14 during temporal pattern formation in

Caenorhabditis elegans (1). Since then, a variety of miRNAs

have been discovered. More than 500 miRNAs have been

cloned and sequenced in humans, and the estimated number of

miRNA genes is as high as 1,000 in the human genome (2).

miRNAs are estimated to regulate the expression of more than

a third of human protein-coding genes (3). Therefore, miRNAs

are important regulators of gene expression in various disease

and development processes. Initially, the importance of miR-

NAs is mainly discussed in regulating oncogenesis and tumor

suppression. Altered patterns of miRNAs expression may

increase cell proliferation and decrease apoptosis to involve

cancer initiation and progression (4). Recently, since 2005, the

exciting research on the biological roles of miRNAs in the

mammalian cardiovascular system has become a most rapidly

evolving field. Several studies have demonstrated the impor-

tance of miRNAs not only in cardiovascular development, but

also in cardiovascular disease (5–8). In the present article, the

currently relevant findings on the role of miRNAs in cardiac hy-

pertrophy and heart failure will be summarized and the target

genes and signaling pathways linking these miRNAs in the con-

text will be discussed.

In mammals, the majority of miRNAs are located within

introns of either protein-coding or noncoding host genes (9).

miRNAs are initially transcribed as long RNA precursors

called primary miRNAs that requires the RNase III enzyme

Drosha in the nucleus to be trimmed into premature miRNAs

(Fig. 1). The latter precursor, characterized by a 33-nt stem-

loop or hairpin structure of 60–70-nt, are exported to the cyto-

plasm where they are subsequently cropped to become mature

miRNAs of 21–26-nt in length, by another RNase III enzyme

Dicer. One strand of the mature miRNA is incorporated in the

so-called miRNA-induced silencing complex (miRISC). Inter-

action with miRNA recognition elements that are mainly

located in the 30-untranslated region (UTR) of target messen-

ger RNAs leads to the degradation or translational inhibition

with subsequent protein repression (10). On the one hand, if

the pairing between the guide miRNA and the target RNA is

imperfect, then the RISC complex will inhibit the protein

translation of that RNA. On the other hand, if there is a per-

fect match, then the target mRNA will be cleaved (11).

Address correspondence to: Prof. Tongcun Zhang, College of Bio-

technology, Tianjin University of Science and Technology, Tianjin

300457, China. Tel: 186 2260 602 099. Fax: 186 2260 602 298.

E-mail: tony@tust.edu.cn

Received 18 February 2009; accepted 9 March 2009

ISSN 1521-6543 print/ISSN 1521-6551 online

DOI: 10.1002/iub.204

IUBMB Life, 61(6): 566–571, June 2009

Nucleotides 2 through 8 at the 50 end of the miRNA, termed

the seed sequence, are the most important determinants of

mRNA target selection. However, other nucleotides and

mRNA secondary structure in the regions surrounding the tar-

get sequence also influence the association of miRNAs with

their targets (3). It has been predicted that each single miRNA

can have [1,000 target genes and each single protein-coding

gene can be regulated by multiple miRNAs (3).

SPECIFIC EXPRESSION PROFILE OF MIRNA IN THEHEARTS

The expression profile of miRNAs seems to be tissue-cell

specific. Cheng et al. have implemented microarray technology

to analyze the expression of hundreds of miRNA in the normal

mouse (C576BJ) hearts (12). Overall, 157 of 233 arrayed miR-

NAs were found in normal mouse hearts, and 64 of these were

highly expressed. Their data also suggest the miRNA expression

profile in rat carotid artery is different from that in the rat heart.

The different expression profiles in different tissues implied that

the physiological functions of miRNAs in each tissue could be

unique. In addition, miRNA expression profiles can change

during cardiac development, and many miRNAs that are only

normally expressed at significant levels in the fetal human heart

are re-expressed in cardiac disease, such as heart failure. Fur-

thermore, also miRNAs whose expression is not restricted in

the heart may have important cardio-specific factions (13). So

this needs to be tested in the future.

EXPRESSION PROFILES OF miRNAs IN THE CARDIACHYPERTROPHY AND HEART FAILING

In response to injury and stress (such as hypertension, ische-

mic heart disease, aortic stenosis, and endocrine disorders), the

adult heart undergoes hypertrophic growth and cardiac remodel-

ing to compensate for sustaining cardiac output and impairing

cardiac function (14, 15). Cardiac hypertrophy, which is charac-

terized by an increase in cell size and/or myofibrillar without a

change in myocyte number, often leads to heart failure by acti-

vating intracellular signaling pathways and transcriptional medi-

ators in cardiac myocytes. Cardiac hypertrophy is also accompa-

nied by re-activation of ‘‘fetal’’ cardiac genes normally

expressed in the heart before birth (14). Given the emerging

research articles focus on miRNA and cardiac disease, it is

Figure 1. Biogenesis of miRNAs and their molecular mechanism in gene regulation.

567MicroRNAs IN CARDIAC HYPERTROPHY AND HEART FAILURE

therefore reasonable to hypothesize that miRNAs play important

roles in cardiac hypertrophy and heart failure.

Using miRNA microarrays, several groups have found the

global miRNA expression profile in mouse models that were

made hypertrophic by transverse aortic binding (TAB) or trans-

genic calcineurin. Olson identified 28 differentially expressed

miRNAs common to TAC and calcineurin-mediated hypertro-

phy and found that many of these were also overexpressed in

failing human hearts (7). The two models of pathological car-

diac hypertrophy demonstrated that the expression of miRNAs

are both up- and downregulated during differently induced car-

diac hypertrophy. Sayed et al. reported an array of more than

50 microRNAs with expression that progressively changes dur-

ing development of pressure-overload cardiac hypertrophy and

identified miR-1 as among the earliest microRNAs downregu-

lated during hypertrophy (6).

Importantly, miRNA expression profiles during hypertrophic

growth have also been reported to occur in human failing

hearts. Indeed, about more than 80% of induced and repressed

miRNAs were regulated in the same direction in fetal and fail-

ing heart tissue compared with healthy adult control left ven-

tricle (5). The most consistent changes were upregulation of

miR-21, miR-29b, miR-129, miR-210, miR-211, miR-212,

miR-423, and downregulation of miR-30, miR-182, and miR-

526. Clinical studies showed that a total of 43 out of 87 miR-

NAs detected are aberrantly expressed in hearts with ischemic

cardiomyopathy, dilated cardiomyopathy or aortic stenosis

(16). In a recently published article, miRNAs expression pat-

terns are examined in two types of human heart failure: idio-

pathic dilated cardiomyopathy and ischemic cardiomyopathy.

Their results demonstrate that subsets of miRNAs are differen-

tially regulated in each of these disease state etiologies and

each etiology demonstrated dysregulation of unique sets of

miRNAs (17). Taken together, the aforementioned data showed

that miRNAs were aberrantly expressed in hypertrophic hearts

and the results were confirmed by in vitro and in vivo studies

of cardiac hypertrophy.

MicroRNAs AND CARDIAC HYPERTROPHY ANDHEART FAILURE

More profound functions for these microRNAs in cardiac

biology have been revealed by gain- and loss-of-function stud-

ies. The overexpression of some miRNAs that are upregulated

in hypertrophic hearts induces cardiac myocyte hypertrophy,

whereas the overexpression of some miRNAs that are down-

regulated in hypertrophic hearts prevents cardiac myocyte hy-

pertrophy. Olson reported that miR-23a, miR-23b, miR-24,

miR-195, and miR-214, all of which were upregulated during

cardiac hypertrophy, appeared to be capable of inducing cardiac

hypertrophy, appeared to be capable of inducing hypertrophic

growth in cadiomyocytes (7). A transgenic approach revealed

that myocardial overexpression of miR-195 in mice was suffi-

cient to induce pathological cardiac growth and heart failure

within several weeks after birth (Fig. 2). However, the target

genes for miR-195 relevant to hypertrophy have not been stud-

ied. Moreover, the authors found that overexpression of miR-

214, which are also upregulated during hypertrophy, could not

evoke an adverse cardiac remodeling response. These studies

indicated that only some specific miRNAs were key regulators

in cardiac hypertrophy program.

Elegant work from Olson lab demonstrated that miR-208,

encoded by an intron 27 of the a-MHC gene, is required for

cardiomyocyte hypertrophy, fibrosis (18). The study showed

that miR-208 knockout mice are viable and exhibit no apparent

gross developmental defects. However, upon induction of TAC

pressure-overload, the mice had a blunted hypertrophic and

fibrotic response. Moreover, the miR-208-deficient mice failed

to upregulate b-MHC but instead increased a-MHC expression

to compensate. MiR-208 may integrate b-MHC by repressing

the thyroid hormone receptor associated protein 1 (Thrap1), a

cofactor of the thyroid hormone receptor (Fig. 2). The 30UTR

of Thrap1 is targeted directly by miR-208 and Thrap1 protein

levels were elevated in miR-208 null hearts (18).

MiR-21, a miRNA implicated in tumor-related cell growth

and apoptosis (19, 20), is upregulated in response to agonist-

induced cardiac hypertrophy in cell culture experiments and in

pressure-overload induced hypertrophy in vivo. Tatsuguchi et al.

used overexpression and knockdown approaches to demonstrate

that miR-21 repress hypertrophy in neonatal rat cardiomyocyte

in vitro (21). However, another study points to a different role

of miR-21 in cardiac hypertrophy. Cheng et al. reports that inhi-

bition of miR-21 expression is able to decrease cardiac myocyte

hypertrophy stimulated by both (angiotensin II) Ang II and

(phenylephrine) PE (12). Moreover, Thum et al. demonstrated

that miR-21 resulted in the cellular hypertrophy and activation

of a fetal gene program (5). It should be noted that controver-

sies exist among these studies. In 2008, Thum shows that

miRNA-21 regulates the ERK-MAP kinase signaling pathway

in cardiac fibroblasts, which has impacts on global cardiac

structure and function. MiR-21 levels are increased selectively

in fibroblasts of the failing heart, augmenting ERK-MAP kinase

activity through inhibition of sprouty homologue 1 (Spry1)

Figure 2. Diagram depicting the miRNA and their target genes,

which have been reported for their participation in cardiac hy-

pertrophy and heart failure.

568 WANG ET AL.

(Fig. 2) (8). Clearly, further analysis of the molecular pathways

modulated by miR-21 in different biological systems is needed

to better understand the biological function of this miRNA.

Sucharov et al. recently reported the role of miR-100 and

miR-92 in the hypertrophic process by their mimics and inhibi-

tors (17). The expression of miR-100 is increased in the failing

heart. Upregulation of miR-100 in neonatal rat cardiac ventricu-

lar myocytes results in repression of the adult genes aMyHC

and SERCA and increases isoproterenol-mediated upregulation

of the fetal genes ANF and bMyHC. Interestingly, downregula-

tion of miR-100 prevented isoproterenol-mediated repression of

aMyHC and SERCA but not the induction of the fetal isoforms,

suggesting that inhibition of miR-100 specifically regulates

expression of genes involved in ISO-mediated repression of the

adult isoforms. Unlike miR-100, miR-92 is downregulated in

heart failure. Inhibition or upregulation of miR-92 has a

minimal effect on the regulation of fetal or adult gene expres-

sion. These results suggest that the role of miRNAs in heart dis-

ease is specific and not all miRNAs affect global aspects of the

disease.

miR-1 and miR-133, which belong to the same transcrip-

tional unit, are expressed at low levels in mouse and human

models of cardiac hypertrophy (22). Notably, miR-1 and miR-

133 expression was consistently downregulated both in patho-

logical and physiological hypertrophy as demonstrated in mice

subjected to TAC, Akt-overexpressing transgenic mice or exer-

cise-trained wild-type mice, respectively (22). In vitro, overex-

pression of miR-133 or miR-1 inhibited cardiac hypertrophy.

Importantly, in vivo inhibition of miR-133 by a single infusion

of an antimiRNA antisense oligonucleotide (AMO) against

miR-133 caused marked and sustained cardiac hypertrophy.

This occurs through the regulation of different targets: RhoA, a

GDP-GTP exchange protein regulating cardiac hypertrophy;

Cdc42, a signal transduction kinase implicated in hypertrophy;

and Nelf-A (negative elongation factor A)/WHSC2 (Wolf-

Hirschhorn syndrome candidate 2), a nuclear factor involved in

cardiogenesis (Fig. 2) (21). Duisters et al. recently reported that

connective tissue growth factor (CTGF), which is a key mole-

cule in the process of fibrosis, is a direct target of miR-133 and

miR-30 (23).

MiR-1 is specifically expressed in cardiac precursor cells,

and the miR-1 gene is a direct transcriptional target of muscle

differentiation regulators, including SRFs (serum-response fac-

tors), MyoD (myogenic differentiation factor D) and Mef2

(myocyte-enhancing factor 2) (24). Abdellatif’s group found

that miR-1 was singularly downregulated as early as day 1, per-

sisting through day 7, after TAC-induced hypertrophy in a

mouse model (6). Overexpression of miR-1 carried by adenovi-

rus vector inhibited its in silico-predicted growth-related targets,

including Ras guanosine-triphosphatase-activating protein,

cyclin-dependent kinase 9, fibronectin, and Ras homolog

enriched in brain, in addition to protein synthesis and cell size

(Fig. 2). Wagner et al. recently injected the fragments of either

the coding region or the related microRNA miR-1 into fertilized

mouse eggs (25). This microinjecting led to high levels of

expression of homologous RNA, resulting in an epigenetic

defect, cardiac hypertrophy. In this case, paramutation increased

rather than decreased expression of Cdk9.

Both miR-1 and miR-133 are proposed to regulate the

expression of growth-related genes. Intriguingly, a recent report

suggested that miR-1 and miR-133 might also have a distinct

role in the regulation of cardiomyocyte apoptosis: miR-1 seems

to be proapoptotic, whereas miR-133 appears antiapoptotic (26).

Moreover, in cell-based experiments, a recent study shows that

downregulation of miR-133b is sufficient to induce hypertrophic

gene expression while overexpression of miR-133b attenuates

aspects of b-AR-mediated changes in gene expression (17).

These studies show that miR-133 and miR-1 are key regulators

of cardiac hypertrophy, suggesting their fundamental role in the

development of disease and, as such, potential targets and/or

agents of novel therapies.

MicroRNAs AND MYOCARDIAL IFARCTION

Acute myocardial infarction (MI) due to coronary artery

occlusion is accompanied by a pathological remodeling

response that includes hypertrophic cardiac growth and fibrosis,

which impair cardiac contractility. Olson group show that MI in

mice and humans also results in the dysregulation of specific

miRNAs, which are similar to but distinct from those involved

in hypertrophy and heart failure (27). Among the MI-regulated

miRNAs are members of the miR-29 family, which are downre-

gulated in the region of the heart adjacent to the infarct. The

miR-29 family targets a cadre of mRNAs that encode proteins

involved in fibrosis, including multiple collagens, fibrillins, and

elastin. Downregulation of miR-29 with anti-miRs in vitro and

in vivo induces the expression of collagens, whereas overexpres-

sion of miR-29 in fibroblasts reduces collagen expression. So,

miR-29 acts as a regulator of cardiac fibrosis and represents a

potential therapeutic target for tissue fibrosis in general.

MicroRNAs-BASED THERAPEUTICS FOR HEARTDISEASE

The identification of microRNA as important regulators has

led to the development of many ideas by which these micro-

RNAs can be used as tools for disease therapy in the cardiovas-

cular system. First, it is apparent that miRNA expression pat-

terns are dynamically regulated during disease. Thus, it is likely

that miRNA expression patterns will be used for biomarkers or

diagnosis indicators and prognosis, as shown recently for

numerous forms of heart disease. Second, it is also conceivable

that miRNA mimics could be developed to enhance the expres-

sion of beneficial miRNAs. Customized anti-miRs or miR

mimics directed against specific mRNA targets can also be

envisioned. Third, chemically engineered oligonucleotides,

termed ‘antagomirs’ have been developed and proven to be effi-

cient and specific silencers of endogenous miRNAs in mice

569MicroRNAs IN CARDIAC HYPERTROPHY AND HEART FAILURE

(28). Chemical modifications and cholesterol conjugations have

been shown to stabilize and facilitate intravenous delivery of

antagomirs. This approach resulted in a marked reduction of the

corresponding miRNAs in different organs such as liver, lung,

kidney, skin, bone marrow, skeletal, and cardiac muscle. The

silencing effect was considerably sustained over time probably

because of a long half-life of endogenous miRNAs (13, 29).

Antagomirs interact with miRNAs in the cytoplasm and lead to

specific miRNA downregulation when injected systemically or

locally. However, this feature of miRNAs could be a two-edged

sword that brings about ‘off-target’ side effects. It is well

known that single miRNAs are predicted to have multiple

mRNA targets (many into the hundreds). So, specificity of

drug-like oligonucleotides is of great importance to minimize

off-target effects. Toxicity of chemical modifications used to

facilitate cellular uptake and prevent degradation also represents

an important consideration (30). Clearly, caution and future

studies directed at understanding the pathways regulated by car-

diac miRNAs are needed before clinical treatments.

CONCLUSION

Recent studies provide clear evidence that miRNAs modulate

a diverse spectrum of cardiac functions with developmental,

(patho)physiological, and clinical implications. The biology of

miRNAs in cardiovascular disease is a young research area and

an emerging field. Although much progress has been made to-

ward establishing miRNAs as important regulators in cardiovas-

cular biology, we are just beginning to understand this role of

novel gene regulators and further studies were needed. More

importantly, identifying their gene targets and signaling path-

ways responsible for their cardiovascular effects is critical for

future studies. Dissection and characterization of the signaling

pathways leading to cardiac hypertrophy has led to a wealth of

knowledge about this condition both physiological and patho-

logical. The role of miRNAs in the pathogenesis of the heart

and vessel points to a possibility of miRNAs as targets for treat-

ment of cardiovascular disease. Taken together, these recent

reports show that miRNA play a powerful role in cardiovascular

systems and are sure to open the door to previously unappreci-

ated medical therapies.

ACKNOWLEDGEMENTS

This work was financially supported by National Natural Sci-

ence Foundation of China (No.30800561) and Scientific

Research Foundation of Tianjin University of Science and

Technology (20080409).

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571MicroRNAs IN CARDIAC HYPERTROPHY AND HEART FAILURE