REVIEWS

MicroRNAs in myocardial infarction

Reinier A. Boon and Stefanie Dimmeler
Abstract | MicroRNAs (miRNAs) are small noncoding RNAs that block translation or induce degradation
of mRNA and thereby control patterns of gene expression. Acute myocardial infarction is a common
cardiovascular event that results in cardiac remodelling and can consequently lead to the development of
chronic heart failure. Several miRNAs have been shown to control important processes that contribute to
the pathophysiological consequences of acute myocardial infarction. miRNAs can either promote or inhibit
cardiomyocyte cell death, and also regulate postischaemic neovascularization. Cardiac regeneration can
also be regulated by miRNAs that control cardiomyocyte proliferation or interfere with cardioprotective effects
mediated by stem or progenitor cells. miRNAs can also be used for direct reprogramming of cardiac fibroblasts
into cardiomyocytes. In this Review, we focus on the current understanding of the role of miRNAs in these
processes, and particularly discuss the therapeutic potential of miRNAs in treating acute myocardial infarction.
Boon, R.A. & Dimmeler, S. Nat. Rev. Cardiol. 12, 135142 (2015); published online 16 December 2014; doi:10.1038/nrcardio.2014.207

Introduction

Institute for
Cardiovascular
Regeneration, Center
ofMolecular Medicine,
Goethe University,
Theodor-Stern-Kai7,
60590 Frankfurt am
Main, Germany (R.A.B.,
S.D.).
Correspondence to:S.D.
dimmeler@
em.uni-frankfurt.de

MicroRNAs (miRNAs) were discovered in the 1990s, but

miRNA research has quickly grown into a mature and
broad field. To date, miRNAs have been described in virtually all cellular processes and cell types, including those
relevant to the cardiovascular system. Many of the first
miRNAs to be discovered were described as being specific to particular cell types or organs, and cardiac-specific
miRNAs have likewise been identified.1,2 However, the
heart contains many different cell types, and miRNAs that
are not necessarily cardiac-specific are also expressed in
the heart. Even within cardiomyocytes, many miRNAs are
expressed that are also broadly expressed in other cells.
Furthermore, some of the miRNAs that were initially
thought to be cardiac-specific (for example, miR1 and
miR133) were later found to be expressed in other types
of muscle and vascular cells. Nevertheless, many of these
miRNAs control pivotal processes in the heart, including
the response to ischaemic stress.
Acute myocardial infarction (AMI) is a common
cardiovascular event and, although the principal ischaemic episode is often not fatal,3 the damage to myocardial
tissue that is caused by AMI can lead to the development of heart failure. Consequently, developing therapies that induce regeneration or prevent degeneration
of myocardial tissue after AMI is highly clinically rele
vant. In this Review, we summarize the developments
that show the role of miRNAs in the infarcted heart, and
the therapeutic potential of modulating the expression
of these miRNAs. We focus on the regulation of cardiomyocyte apoptosis and angiogenesis in the acute setting.
Competing interests
S.D. is an advisor for miRagen Therapeutics, and owns a patent
on the development of miR92a therapeutics. S.D. and R.A.B.
are inventors on a patent on the development of miR34a
inhibitors for the treatment of cardiovascular disease.

The regulation of fibrosis by miRNAs has been reviewed

previously in the journal.4

Cardiomyocyte survival

A potential intervention to improve cardiac contractile

function after AMI is to induce survival of cardiomyocytes so that, despite a considerable duration of ischaemia,
cell death is prevented. Several miRNAs have been shown
to promote or impair cardiomyocyte survival (Figure1a).

Negative regulators
Members of the miR15 family, which comprises six
closely-related miRNAs, were among the first to be
described as being increased after ischaemia and to
induce cardiomyocyte cell death.5 Inhibition of miR15
family members by short, locked nucleic acid (LNA)based antimiRs (or tiny antimiRs), which are designed to
target the seed sequence and thereby inhibit several family
members (including miR15b, miR16, and miR195),
reduced infarct size after ischaemiareperfusion injury.5
Cell-death-promoting activity of miR15 was attributed to targeting of apoptosis regulator Bcl2, and
mitochondrial-protective function was associated with
repression of ADP-ribosylation factor-like protein2.57
The miR15 family member miR195 was additionally shown to downregulate NAD-dependent protein
deacetylase sirtuin1 (SIRT1), thereby contributing to
cardiomyocyteapoptosis.7
Another miRNA that negatively regulates cell survival was first described in cancer cells.8 The miR34
family, consisting of miR34a, miR34b, and miR34c, is
regulated by cellular tumour antigenp53, and its aberrant expression is a common feature in various cancer
types. The miR34 family is upregulated after AMI and
has been shown to contribute to cardiomyocyte cell
death in both invitro and invivo studies.9,10 Inhibition of

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REVIEWS
Key points
Tissue injury and inflammation regulate microRNAs in the heart after
myocardial infarction
MicroRNAs control many processes in the infarcted heart, such as
cardiomyocyte cell death and proliferation, neovascularization, and
progenitor-cell-mediatedrepair
Acute inhibition or overexpression of microRNAs after myocardial infarction
might be useful to limit tissue injury and improve neovascularization to
preventlong-term negative remodelling and heart failure
Using microRNAs to induce cardiac regeneration by direct cardiac
reprogramming of fibroblasts or by inducing cardiomyocyte proliferation
offersnew therapeutic opportunities

miR-15

miR-34

miR-140

miR-320

Bcl-2
ARL2
SIRT1

PNUTS
SIRT1
POFUT1
BCL-6
SEMA4B

MFN1

Hsp20

Bim
Cardiomyocyte

Proapoptotic
Antiapoptotic

miR-24
miR-19

Cardiomyocyte
apoptosis

miR-214
miR-199a

miR-590

Homer-1
HOPX

PTEN

Chk1

CCND2
TtK
Cdc37
Pa2g4

miR-15

miR-133

Cardiomyocyte
Induce proliferation
Inhibit proliferation

PTEN
CyP-D
Bim
NCX1
CaMKII

Cardiomyocyte
proliferation

Figure 1 | MicroRNAs regulate cardiomyocyte survivalNature

and proliferation.
Reviews | Cardiology
a|Cardiomyocyte apoptosis. Several microRNAs regulate apoptosis and
survivalpathways in cardiomyocytes. Inhibition of apoptosis or activation
ofsurvival programmes enhances cardiac regeneration. Proapoptotic microRNAs
include the miR15 family, miR34, miR320, and miR140. Antiapoptotic
microRNAs include miR24 and miR214. b | Cardiomyocyte proliferation.
Theproliferative capacity of cardiomyocytes is very limited, but induction of
proliferation enhances cardiac regeneration. MicroRNAs from the miR17~92
cluster, as well as miR199a and miR590, induce proliferation of cardiomyocytes,
whereas miR15 and miR133 inhibit proliferation of cardiomyocytes.
Abbreviations: ARL2, ADP-ribosylation factor-like protein2; Bcl2, apoptosis
regulator Bcl2; BCL6, Bcell lymphoma6 protein; Bim, protein Bim (also known
as Bcl2-like protein11); CaMKII, calcium/calmodulin-dependent protein kinase
typeII subunit; CCND2, G1/Sspecific cyclinD2; Cdc37, cell division cycle37
homologue; Chk1, serine/threonine-protein kinaseChk1; CyPD, cyclophilinD
(also known as mitochondrial peptidyl-prolyl cis-trans isomeraseF); Homer1,
Homer protein homologue1; HOPX, homeodomain-only protein; Hsp20, heat
shock protein20 (also known as heat shock protein6); MFN1, mitofusin1;
miR,microRNA; NCX1, sodium/calcium exchanger1; Pa2g4; novel protein similar
to human proliferation-associated 2D4 protein (PA2G4); PNUTS, serine/
threonine-protein phosphatase1 regulatory subunit10 (PPP1R10); POFUT1,
GDPfucoseprotein O-fucosyltransferase1; PTEN, phosphatidylinositol
3,4,5trisphosphate 3phosphatase and dual-specificity protein phosphatase
PTEN; SEMA4B, semaphorin4B; SIRT1, NAD-dependent protein deacetylase
sirtuin1; Ttk, dual specificity protein kinaseTtk.

136 | MARCH 2015 | VOLUME 12

miR34 expression invivo using LNA-based antimiRs or

antagomiRs improved cardiomyocyte survival after AMI,
and thereby preserved cardiac contractile function.9,10
miR34a inhibition also improved cardiac function
after moderate hypertrophic cardiomyopathy.11 Of note,
miR34 is also upregulated in mammalian (including
human) hearts during ageing.9 Furthermore, inhibition or
deletion of miR34a ameliorated ageing-induced cardiac
dysfunction.9 Mechanistically, miR34 was shown to target
multiple mRNAs of genes that promote cell survival.9,10,12
SIRT1 was one of the first targets to be identified, and is
known to enhance cardiac function after AMI.12 Targets
that were previously not known to have a role in cardio
myocyte survival include Bcell lymphoma6 protein
(BCL6), GDPfucose protein Ofucosyltransferase1
(POFUT1), serine/threonine-protein prosphatase1 regulatory subunit10 (PPP1R10; also known as PNUTS),9 and
semaphorin4B (SEMA4B).10 PNUTS has been shown to
preserve cardiac function after AMI when overexpressed
in cardiomyocytes.9
miRNA320 was shown to be downregulated after
ischaemiareperfusion in mice. 13 Data from invitro
studies showing that miR320 increased cardiomyocyte
cell death were confirmed by invivo studies involving
transgenic mice overexpressing miR320 in cardiomyocytes.13 By contrast, silencing of miR320 reduced infarct
size after ischaemiareperfusion invivo. Using proteomic
approaches and insilico prediction tools, the investigators showed that targeting of heat shock protein6 (also
known as heat shock protein20), a known cardioprotective
protein, contributed to the detrimental effects ofmiR320.13
Subsequent studies have provided an additional link
between miRNAs and mitochondrial morphology, which
is crucial for tissue homeostasis. miR140 was shown to
reduce mitochondrial fission by targeting mitofusin1.14
Consistently, inhibition of miR140 reduced myocardial
infarct size invivo.14 Furthermore, various miRNAs have
been shown to induce or aggravate cardiomyocyte cell
death invitro, including miR1/miR206,15 miR92a,16,17
miR122,18 miR150,19 miR181a,20 and miR376b5p.21

Protective regulators
miR24, a member of the miR23/24/27 cluster, was
reported as being a cardiomyocyte-protective miRNA
invitro,22,23 and miR24 overexpression invivo was found
to attenuate infarct size and improve heart function after
AMI,23 even though cardiomyocyte-specific overexpression of miR24 was embryonically lethal in mice.24 The
cardiomyocyte-protective effect was attributed to targeting of the proapoptotic Bcl2-like protein11 (also
known as Bim).22,23 However, the regulation and function of miR24 after ischaemia are complicated: miR24
is downregulated in cardiomyocytes and fibroblasts
after AMI,23 but was shown to be increased by hypoxia
in cultured cardiomyocytes.25 Moreover, miR24 exhibited antiangiogenic effects26,27 and impaired excitation
contraction coupling.22 By these mechanisms, miR24
inhibition improved neovascularization and cardiac function after ischaemia,22,27 thereby raising concerns about
the use of miR24 overexpression as a therapeuticstrategy.

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REVIEWS
Among miRNAs that are upregulated after cardiac
stress, miR214 has a protective function.28 Overexpres
sion of this miRNA protected against H 2O2-induced
cardiomyocyte apoptosis,29 whereas genetic deletion of
miR214 aggravated cell death induced by ischaemia
reperfusion, and caused deterioration of heart function.28 Targets of miR214 include the sodium/calcium
exchanger1, which contributes to calcium overload
under stress conditions;28 cyclophilinD (also known as
mitochondrial peptidyl-prolyl cis-trans isomeraseF),
a regulator of the mitochondrial permeability transition pore; the proapoptotic Bcl2-like protein11 (Bim);
calcium/calmodulin-dependent protein kinase typeII
subunit, which regulates hypertrophy; and PTEN
(phosphatidylinositol 3,4,5trisphosphate 3phosphatase
and dual-specificity protein phosphatase PTEN), a phosphatase inhibiting PI3K/Akt signalling 29all of which
might contribute to the observed protective effect of
this miRNA.28,29 Despite evidence for a cardioprotective
function, other data have suggested that chronic
cardiomyocyte-specific overexpression of miR214
induces dilated cardiomyopathy via interference with the
polycomb repressor complex protein EZH2 (histone
lysine Nmethyltransferase EZH2).29 The reasons for
these differences are uncertain, but transient induction of
miR214 after AMI might provide a short-term protective
effect, whereas long-term, chronic overexpression might
induce pathological processes. In additional cell-culture
studies, miR7a/b,30 miR20a,31 miR138,32 miR144/451,33
miR210, 34 miR499, 35 and miR874 36 were found to
inhibit apoptosis of cardiomyocytes.

Cardiomyocyte proliferation

In contrast to, for example, liver and skin, the heart does
not regenerate well. In part, this deficit is owing to the
very limited proliferative capacity of cardiomyocytes.
Therefore, the induction of cardiomyocyte proliferation
might contribute to therapeutic cardiac regeneration
(Figure1b).37,38 Cardiomyocytes retain their proliferative
capacity for only a short postnatal period (<7days) in
mice, and hearts can regenerate after damage during this
period.39 miRNA expression profiling of hearts of neonatal mice in this regenerative window showed that one
miRNA family in particularthe miR15 family (including miR15a, miR15b, miR16, miR195, and miR497)
was expressed at low levels just after birth, and induced
at the time when cardiomyocytes lost their capacity to
proliferate.40 Inhibition of miR15b and miR16 prolonged the period during which mouse cardiomyocytes
could proliferate after birth, as a result of induction of
checkpoint kinase1 (also known as serine/threonineprotein kinaseChk1), which is involved in mitotic
progression.40,41 miR195 transgenic mice had cardiac
malformations and a decrease in heart size atbirth.41
Other miRNAs have been shown to affect the proliferative capacity of cardiomyocytes. In an elegant highthroughput overexpression approach in which 875
miRNAs were tested, ectopic expression of two miRNAs
in particular (miR199a and miR590) induced proliferation in neonatal rat cardiomyocytes.42 Both these miRNAs

inhibit the expression of many negative regulators of

the cell cycle, including Homer protein homologue1
and homeodomain-only protein.42 Adeno-associated
virus9-mediated overexpression of miR199a and miR590 induced proliferation of cardiomyocytes in adult mice
and stimulated cardiac regeneration afterAMI.42
One of the first miRNAs to be described as being
cardiac-enriched, miR133a, was shown to inhibit proliferation of cardiomyocytes.43 In one study, genetic deletion of both copies of miR133a was embryonically lethal
in half of the mice, whereas the surviving mice developed
cardiomyopathy and heart failure owing to aberrant proliferation.43 Depletion of miR133 in zebrafish also induced
cardiomyocyte proliferation and enhanced regeneration of
the heart, whereas transgenic miR133 expression inhibited this process.44 The cell-cycle regulators G1/Sspecific
cyclinD2 in mice, and dual specificity protein kinase TTK,
cell division cycle37 homologue, and novel proteinsimilar
to human proliferation-associated 2G4 protein (PA2G4) in
zebrafish, are targets of miR133 and at least partly explain
the effects of miR133 onproliferation.43,44
In particular, the miR17~92 cluster, consisting
ofmiR17, miR18a, miR19a, miR19b, miR20a, and
miR92a, was shown to induce proliferation of cardio
myocytes. 45 Cardiomyocyte-specific deletion of this
cluster resulted in reduced cardiomyocyte proliferation
and heart weight at birth, whereas cardiomyocyte-specific
miR17~92 knock-in mice had bigger hearts at birth.45
Enhanced cardiomyocyte proliferation persisted in adult
mice, contributing to an improvement in cardiac recovery
after AMI.45 The main target of the miR17~92 cluster was
shown to be PTEN, a negative regulator of survivaland
proliferation, which is downregulated by miR19a
and miR19b. However, overexpression ofmiR17~92
can also induce arrhythmias and hypertrophy.46 The
arrhythmias might be caused by the aberrant repression
of connexin43 (also known as gap junction1 protein)
by miR19a and miR19b.46 Therefore, the effects of
miR17~92 on proliferation and arrhythmias are likely to
be caused predominantly by miR19a and miR19b. The
function of the other family members warrants detailed
studycardiomyocyte-specific deletion of miR92a, for
example, was shown to have a modest protective effect
after AMI.17

Angiogenesis

Functional regeneration of cardiac tissue, which has

an inherently high metabolic activity, requires cardiomyocytes to have a sufficient blood supply. Therefore,
the growth of new blood vessels, termed angiogenesis,
is essential for the process. Several miRNAs have been
described to affect angiogenesis (Figure2), although
most have not been studied in the heart.
Members of the miR17~92 cluster control angio
genesis and neovascularization after AMI.47 miR92a was
shown to inhibit endothelial-cell migration and sprouting in cell-culture studies.47,48 Invivo, pharmacological
inhibition of miR92a using antagomiRs increased capillary density and improved heart function after AMI in
mice.47,48 Genetic deletion of miR92a also augmented

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Angiogenic
Antiangiogenic

miR-15

miR-24

VEGFA
AKT3
FGF2
eNOS
GATA-2
PAK4

SMAD1

miR-26

Integrin 5
KLF2
SIRT1

miR-92a

Ephrin-A3
PTP-1B

miR-210

Figure 2 | MicroRNAs regulate angiogenesis. Angiogenesis is crucial to the supply

Nature Reviews | Cardiology
of (regenerated) cardiac muscle with oxygen and nutrients. Several microRNAs
have been described to induce or repress angiogenesis. For example, miR15,
miR24, miR26, and microRNAs from the miR17~92 cluster are antiangiogenic,
via inhibition of endothelial-cell function. Conversely, miR210 induces
angiogenesis by inhibiting antiangiogenic factors. Abbreviations: AKT3, RAC
serine/threonine-protein kinase; eNOS, endothelial nitric oxide synthase; FGF2,
fibroblast growth factor2; GATA2, endothelial transcription factor GATA2;
KLF2,Krppel-like factor2; PAK4, serine/threonine-protein kinasePAK4; miR,
microRNA;PTP1B, tyrosine-protein phosphatase non-receptor type1; SIRT1,
NADdependent protein deacetylase sirtuin1; SMAD1, mothers against
decapentaplegic homologue1; VEGFA, vascular endothelial growth factorA.

recovery after AMI in mice.17 In a preclinical, largeanimalstudy, catheter-based delivery of antimiR92a

reduced infarct size.17 Although this study showed a
significant upregulation of capillary density, whether
the cardioprotective effect observed 47days after
ischaemiareperfusionwas solely a result of increased
angiogenesis is uncertain; a direct ca rdiomyocyteprotective effect might also have contributed.17 The
targets bywhich miR92a elicits its effects include integrin5,47 whichprevents endothelial-cell apoptosis and
is important for vessel maturation.49 In addition, several
vasculoprotective genes are repressed by miR92a, such as
KLF2 and SIRT1.50 The function of other members of the
miR17~92 cluster, such as miR20a, on vascularization
is less well-defined, given that inhibition of miR20a has
been shown either to promote51,52 or block53 endothelialcell proliferation and migration. Deletion of the paralogue
miR106b~25 cluster also reduced neovascularization
after hind-limb ischaemia via derepression of PTEN
expression54 (which is also targeted by miR19), suggesting that some members of the miR17~92a and paralogue
clusters have proangiogeniceffects.
Inhibition of miR24 improved neovascularization
in two studies. AntagomiRs directed against miR24
or local adenovirus-mediated miR24 decoy delivery
improved the recovery after AMI in mice by derepressing
138 | MARCH 2015 | VOLUME 12

endothelial nitric oxide synthase, endothelial transcription factor GATA2, and serine/threonine-protein
kinasePAK4.26,27 These data indicate that miR24 inhibition might be an attractive therapeutic strategy; however,
the proapoptotic effect on cardiomyocytes observed
after miR24 inhibition (even in the studies documenting a therapeutic benefit of treatment 26) suggests that
cellspecifc targeting strategies might be necessary.
miR26a is also increased after AMI and inhibits
angiogenesis invitro and invivo.55 Overexpression in
zebrafish inhibited formation of the caudal vein plexus,
and exercise-induced angiogenesis was blocked in mice.55
Administration of an LNA-based antimiR induced robust
angiogenesis, reduced myocardial infarct size, and
improved heart function.55 The mechanism was related to
inhibition of bone morphogenic protein/SMAD1 signalling by repressing SMAD1, which resulted in decreased
expression of DNA-binding protein inhibitorID1 and an
increase in the cell-cycle inhibitors p21 (cyclin-dependent
kinase inhibitor1) and p27 (cyclin-dependent kinase
inhibitor1B).
Members of the miR15 family not only induced
cardiomyocyte cell death and reduced cardiomyocyte
proliferation, but also inhibited angiogenesis, via targeting of the well-characterized proangiogenic and endothelial survival factors vascular endothelial growth factorA,
fibroblast growth factor2, and RAC serine/threonineprotein kinase (also known as protein kinaseAkt3).56,57
On the basis of these detrimental effects on cardiomyocytes and vascularization, inhibition of miR15 might be
an attractive strategy to improve recovery after ischaemia
and prevent postischaemic heart failure.
miR210 also elicits effects on cardiomyocytes and the
vasculature. This miRNA is induced by hypoxia58 and
upregulated after AMI.34 miR210 overexpression invitro
or by intramyocardial injection of minicircle vectors
(small ~4kb circular plasmid derivatives) carrying the
miR210 precursor reduced cell death and improved
cardiac function and angiogenesis after AMI.34 miR210
was shown to target the antiangiogenic receptor tyrosine
kinase ephrinA334 and the proapoptotic t yrosine-protein
phosphatase non-receptor type1.34

Repair by progenitor or stem cells

The therapeutic application of various types of cells,

including progenitor cells derived from adult heart,
bone marrow, or adipose tissue, has been shown to have
cardioprotective effects in experimental models of AMI
and in some clinical trials.59,60 However, the establishment of successful cell therapies is challenging owing to
poor homing and survival of the implanted cells, and
a limited cardiac differentiation capacity of most types
of adult progenitor cells. miRNAs have been shown to
modulate such processes, and might be used to enhance
the therapeutic benefits of cell therapy (Figure3).
miR126 overexpression augmented the survival and
migration of mesenchymal stromal cells and proangiogenic bone-marrow-derived cells, and improved the
cardiac-repair capacity of transplanted cells.61,62 This
effect might result from a direct improvement of cell

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REVIEWS
Cell-to-cell communication

miR-1
miR-499

miR-126

miR-155

miR-126

Stem or
progenitor
cells

miR-210

miR-132

miR-15
miR-21
miR-24
miR-221

miR-34

Infarct
area

miR-146

miR-21*

Extracellular
vesicles

Figure 3 | MicroRNAs control the function of stem and progenitor

cells and
are
Nature Reviews
| Cardiology
usedfor intercellular communication. Regeneration of the heart can be induced by
treatment with stem or progenitor cells that contribute to newly formed tissue or
stimulate endogenous cardiac regeneration via paracrine actions. MicroRNAs that
inhibit the function of stem or progenitor cells include the miR15 family and miR34.
Conversely, miR1, miR21, miR24, miR126, miR155, miR221, and miR499
enhance the function of stem or progenitor cells via various mechanisms. Cell-to-cell
communication via microRNAs that are contained in extracellular vesicles or protein
complexes also contributes to endogenous regeneration. Delivery of miR126,
miR132, miR146, and miR210 stimulates cardiac regeneration, whereas miR21*
(miR213p) inhibits cardiac function. Abbreviation: miR, microRNA.

survival via increased PI3K/Akt signalling, or be caused

by enhanced paracrine activities of injected miR126
overexpressing cells, or a combination of both. 63,64
Additionally, miR155 protected cardiac stem cells, and
overexpression prevented necrosis invitro.65
miR34a has exhibited detrimental effects not only
in the heart, but also in bone-marrow-derived cells.
Inhibition of miR34 improved cell survival and function
invitro and invivo by interference with cell-cycle regulators and apoptosis regulator Bcl2.66 Likewise, miR15a
and miR16 harmed progenitor cells, and inhibition of
these miRNAs improved neovascularization in a model
of hind-limb ischaemia.57
miRNAs might also be applied in combination to
elicit synergistic effects. For example, combinations of
miR21, miR24, and miR221 efficiently improved cell
engraftment and survival of transplanted cardiac progenitor cells, in part by repressing the apoptotic Bcl2-like
protein11(Bim).67
Cardiac-enriched miRNAs, such as miR1 and miR499,
have also been shown to contribute to cardiacdif
ferentiation, and their overexpression increased cardiac
lineage commitment of pluripotent stem cells (reviewed
previously 68). These findings stimulated the idea of using
miRNAs to augment reprogramming of fibroblasts to
cardiomyocytes. Indeed, overexpression ofcardiacenriched miR1, miR133, miR208, and miR499 in
combination with pharmacological inhibition of the Janus
kinase (JAK) pathway was sufficient to augment cardiac
gene expression in fibroblasts invitro.69 Similarly, cardiacenriched miRNAs, such as miR1 and miR133, have
been shown to augment transcription-factor-induced
cardiac reprogramming of human fibroblasts invitro.70
The overexpression of this miRNA combination was also
shown to increase the generation of cardiomyocyte-like
cells invivo,69 and increase cardiac function after infarction.71 Reprogramming of fibroblasts with a combination
of transcription factors has been shown to reduce infarct
size and attenuate cardiac dysfunction in mice.72

miRNAs can be transmitted between cells via multiple

carriers and pathways. Carriers that transport miRNAs
include extracellular vesicles (exosomes, shedding vesicles, and apoptotic bodies) and protein complexes,73 but
miRNAs can also be transferred via gap junctions, as
shown by the communication between cardiomyocytes
and cardiac stem cells.74 In the cardiovascular system,
atheroprotective miRNAs can transfer from endothelial
cells to smooth muscle cells via extracellular vesicles or
protein complexes, and thereby regulate the contractile
phenotype of smooth muscle cells (Figure3).75,76 The contribution of exosomes, and specifically cell-to-cell communication via miRNAs, to recovery after AMI was shown
for CD34+ cells, which release exosomes that are particularly enriched in proangiogenic miR126 and improve
neovascularization after ischaemia.77,78 Other investigators
showed that cardiac progenitor cells inhibited apoptosis
of mature cardiomyocytes via extracellular vesicles carrying miR210.79 A combination of cardiac-progenitor-cell
treatment and endothelial-derived exosomes enriched in
miR126 and miR210, to ensure cardiac-progenitor-cell
survival, resulted in an increase in cardiac function in a
mouse model of AMI.80 Furthermore, the same vesicles
also carried miR132, which induced angiogenesis via
inhibition of RAS GTPase-activating protein1 (also
known as Ras p21 protein activator) in targeted endothelial cells.81 Together these mechanisms contributed to
enhanced cardiac regeneration and function after AMI.79
Cardiosphere-derived cardiac stem cells were reported
to employ a similar mechanism to mediate cardioprotection.82 Exosomes isolated from the supernatants of the
cells inhibited apoptosis, promoted proliferation of cardio
myocytes, and augmented angiogenesis; these effects were
partially attributed to the transfer of miR146a.83 Injection
of exosomes or miR146 mimics into injured mouse hearts
recapitulated the regenerative and functional effects
observed after transplantation of cardiospheres, suggesting that exosome-mediated transport of miR146a mediated at least part of the cardioprotective and regenerative
effects of cardiac stem-cell therapy. The anti-inflammatory
properties and endothelial protective effects of miR14683
might additionally have contributed to the observed therapeutic benefits of cardiosphere-derived exosomes. Other
investigators have consistently reported cardioprotective
effects of exosomes derived from cardiac progenitor cells;
however, different miRNAs were reported to mediate the
effects, including miR451.84 Whether the mechanisms
underlying the protective effects of exosomes derived from
progenitor or cardiac stem cells are associated with different preparations, or whether a combination of miRNAs
(and other factors) might mediate the cardioprotective
effect, is unknown.
Of note, other cells have also been shown to secrete
cardioprotective miRNAs. Human pericyte progenitor
cells not only secrete proangiogenic factors, such as vascular endothelial growth factorA, angiopoietin1, and
chemokines, but also release proangiogenic miR132.81
Transcription factor GATA4-overexpressing mesenchymal
stromal cells released miR221-containing microvesicles,

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and thereby reduced cardiomyocyte cell death invitro.85
Cardiac fibroblasts have also been shown to regulate
cardiomyocyte behaviour, including hypertrophy, via
transfer of miR21* (miR213p).86 These endogenous
delivery pathways might be therapeutically exploited
to deliver miRNAs, possibly even in a cell-type-specific
manner, to stimulate regeneration.

Clinical perspectives and challenges

Before miRNA therapeutics can be translated into the clinical setting, large-animal studies are required. Therapeutic
inhibition using miR15 and miR92a has been demonstrated in pig models of myocardial infarction and remodelling,5,16,87 but other promising candidate miRNAs have
not been studied in large-animal models to date.
The development of miRNA therapeutics also involves
some challenges.88 Many of the miRNAs that might be
considered as therapeutic targets for heart disease are
also involved in other disease processes, such as cancer.
For example, miR34 inhibition augments cardiac repair,
but might also induce oncogenesis.8 Many tumours lose
miR34 expression, and the re-expression of miR34
(miR34 replacement therapy) in tumours seems a promis
ing therapy against, for example, liver cancer.89,90 Whether
short-term inhibition of miR34 after AMI increases the
risk of tumourigenesis remains to be established. Con
versely, patients receiving miR34 replacement therapy
might have an increased risk of cardiac diseases, which
should be well monitored. Furthermore, miR15 is known
to be involved in cancer,91 but its inhibition enhances
cardiac regeneration.40,41
Whereas a few miRNAs are specifically expressed in
one cell type (such as miR208 in cardiomyocytes), most
are broadly or ubiquitously expressed in many tissues and
cell types, which raises concerns about adverse effects of
miRNA therapeutics that are systemically applied. Offtarget effects of miRNAs might be circumvented by tissuespecific or cell-type-specific targeting. One method of
enriching miRNA therapeutics in the heart is to infuse
antimiRs or miRNA mimics via catheters. Whereas antegrade or retrograde catheter-based delivery of LNA-based
antimiRs does not fully prevent inhibition of the target
miRNA in other tissues,16 intracoronary application of
1.

2.

3.

4.

5.

6.

Lee, R.C. & Ambros, V. An extensive class of

small RNAs in Caenorhabditis elegans. Science
294, 862864 (2001).
Lagos-Quintana, M. etal. Identification of tissuespecific microRNAs from mouse. Curr. Biol. 12,
735739 (2002).
Members, W.G. etal. Heart disease and stroke
statistics2012 update: a report from the
American Heart Association. Circulation 125,
e2e220 (2012).
Thum, T. Noncoding RNAs and myocardial
fibrosis. Nat. Rev. Cardiol. 11, 655663
(2014).
Hullinger, T.G. etal. Inhibition of miR15 protects
against cardiac ischemic injury. Circ. Res. 110,
7181 (2012).
Nishi, H. etal. MicroRNA15b modulates cellular
ATP levels and degenerates mitochondria via Arl2
in neonatal rat cardiac myocytes. J. Biol. Chem.
285, 49204930 (2010).

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antagomiRs encapsulated in poly(lactic-co-glycolic acid)

(PLGA)-microspheres produced cardiac-specific delivery in pigs.87 Another approach is to activate the antimiR
selectively in the target tissue, for example by local, lightinduced activation of caged antimiRs, which has been
demonstrated invitro. 92 However, cell-type-specific
delivery tools might need to be developed for some
miRNAs, such as miR24, which has divergent effects in
vascular versus cardiac cells. Intracoronary delivery of
microsphere-packaged miRNA inhibitors might be used
to target capillaries.87
Another challenge is to achieve overexpression
ofmiRNAs in the cardiovascular system. Doublestranded miRNA mimics can elicit a nonspecific interferon response, and delivery vehicles, such as liposomes,
are necessary to achieve sufficient uptake. Experimental
studies have shown overexpression of miRNAs in the
vasculature after liposomal delivery, but no large-animal
data are so far available. Lentiviruses, adenoviruses, or
adeno-associated viruses might be alternatives,42 and
additionally solve the problem of cell-type-specific delivery, because adeno-associated virus9 vectors preferentially target cardiomyocytes.93 Finally, given that many
of the miRNAs discussed in this Review potentially have
synergistic effects, the optimal therapeutic benefit might
be achieved by combining several antimiRs or miRNA
mimics. However, such a combinatorial approach might
increase off-target or adverse effects of the therapy, and
complicate the regulatory aspects of clinical development.

Conclusions

In conclusion, ample data suggest that miRNAs critically control the pathophysiological processes after
AMI. Several miRNAs might be attractive candidates
or targets to improve recovery after AMI. In particular,
the acute inhibition or overexpression of miRNAs after
myocardial infarction might be useful to limit tissue
injury, improve neovascularization, and prevent subsequent negative cardiac remodelling that can lead to heart
failure. The use of miRNAs to produce cardiac regeneration by direct cardiac reprogramming of fibroblasts or
by inducing cardiomyocyte proliferation also offers new
therapeuticopportunities.

7.

Zhu, H. etal. MicroRNA195 promotes palmitateinduced apoptosis in cardiomyocytes by downregulating Sirt1. Cardiovasc. Res. 92, 7584
(2011).
8. Hermeking, H. The miR34 family in cancer and
apoptosis. Cell Death Differ. 17, 193199 (2010).
9. Boon, R.A. etal. MicroRNA34a regulates cardiac
ageing and function. Nature 495, 107110
(2013).
10. Bernardo, B.C. etal. Therapeutic inhibition
ofthe miR34 family attenuates pathological
cardiac remodeling and improves heart function.
Proc. Natl Acad. Sci. USA 109, 1761517620
(2012).
11. Bernardo, B.C. etal. Silencing of miR34a
attenuates cardiac dysfunction in a setting
ofmoderate, but not severe, hypertrophic
cardiomyopathy. PLoS ONE 9, e90337 (2014).
12. Yamakuchi, M., Ferlito, M. & Lowenstein, C.J.
miR34a repression of SIRT1 regulates

13.

14.

15.

16.

17.

apoptosis. Proc. Natl Acad. Sci. USA 105,

1342113426 (2008).
Ren, X.P. etal. MicroRNA320 is involved in the
regulation of cardiac ischemia/reperfusion injury
by targeting heat-shock protein20. Circulation
119, 23572366 (2009).
Li, J. etal. Mitofusin1 is negatively
regulatedby microRNA140 in cardiomyocyte
apoptosis. Mol.Cell. Biol. 34, 17881799
(2014).
Shan, Z.X. etal. miR1/miR206 regulate Hsp60
expression contributing to glucose-mediated
apoptosis in cardiomyocytes. FEBS Lett. 584,
35923600 (2010).
Zhang, B. etal. MicroRNA92a inhibition
attenuates hypoxia/reoxygenation-induced
myocardiocyte apoptosis by targeting Smad7.
PLoS ONE 9, e100298 (2014).
Hinkel, R. etal. Inhibition of microRNA92a
protects against ischemia/reperfusion

www.nature.com/nrcardio
2015 Macmillan Publishers Limited. All rights reserved

REVIEWS

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

injuryinalarge-animal model. Circulation 128,

10661075 (2013).
Huang, X. etal. Expression of microRNA122
contributes to apoptosis in H9C2 myocytes.
J.Cell. Mol. Med. 16, 26372646 (2012).
Li, X. etal. MicroRNA150 aggravates H2O2induced cardiac myocyte injury by downregulating cmyb gene. Acta Biochim. Biophys. Sin.
45, 734741 (2013).
Wang, L. etal. Effects of downregulation of
microRNA181a on H2O2-induced H9c2 cell
apoptosis via the mitochondrial apoptotic pathway.
Oxid. Med. Cell. Longev. 2014, 960362 (2014).
Pan, Z. etal. M3 subtype of muscarinic
acetylcholine receptor promotes
cardioprotection via the suppression of
miR376b5p. PLoS ONE 7, e32571 (2012).
Li, R.C. etal. In vivo suppression of
microRNA24 prevents the transition toward
decompensated hypertrophy in aorticconstricted mice. Circ. Res. 112, 601605
(2013).
Qian, L. etal. miR24 inhibits apoptosis and
represses Bim in mouse cardiomyocytes. J. Exp.
Med. 208, 549560 (2011).
van Rooij, E. etal. A signature pattern of stressresponsive microRNAs that can evoke cardiac
hypertrophy and heart failure. Proc. Natl Acad.
Sci. USA 103, 1825518260 (2006).
Li, D.F. etal. Induction of microRNA-24 by
HIF-1protects against ischemic injury in rat
cardiomyocytes. Physiol. Res. 61, 555565
(2012).
Meloni, M. etal. Local inhibition of microRNA24
improves reparative angiogenesis and left
ventricle remodeling and function in mice with
myocardial infarction. Mol. Ther. 21, 13901402
(2013).
Fiedler, J. etal. MicroRNA24 regulates vascularity
after myocardial infarction. Circulation 124,
720730 (2011).
Aurora, A.B. etal. MicroRNA214 protects the
mouse heart from ischemic injury by controlling
Ca2+ overload and cell death. J. Clin. Invest. 122,
12221232 (2012).
Lv, G. etal. MicroRNA214 protects cardiac
myocytes against H2O2-induced injury. J. Cell.
Biochem. 115, 93101 (2014).
Li, B. etal. MicroRNA-7a/b protects against
cardiac myocyte injury in ischemia/reperfusion by
targeting poly(ADP-ribose) polymerase. PLoSONE
9, e90096 (2014).
Frank, D. etal. MicroRNA20a inhibits stressinduced cardiomyocyte apoptosis involving its
novel target Egln3/PHD3. J. Mol. Cell. Cardiol. 52,
711717 (2012).
He, S. etal. miR138 protects cardiomyocytes
from hypoxia-induced apoptosis via MLK3/JNK/
cjun pathway. Biochem. Biophys. Res. Comm.
441, 763769 (2013).
Zhang, X. etal. Synergistic effects of the
GATA4mediated miR144/451 cluster in
protection against simulated ischemia/
reperfusion-induced cardiomyocyte death. J. Mol.
Cell. Cardiol. 49, 841850 (2010).
Hu, S. etal. MicroRNA210 as a novel therapy for
treatment of ischemic heart disease. Circulation
122 (Suppl.), S124S131 (2010).
Wang, J. etal. miR499 protects cardiomyocytes
from H2O2-induced apoptosis via its effects
onPdcd4 and Pacs2. RNA Biol. 11, 339350
(2014).
Wang, K. etal. miR874 regulates myocardial
necrosis by targeting caspase8. Cell Death Dis.
4, e709 (2013).
Porrello, E.R. & Olson, E.N. A neonatal blueprint
for cardiac regeneration. Stem Cell Res. 13,
556570 (2014).

38. Steinhauser, M.L. & Lee, R.T. Regeneration

ofthe heart. EMBO Mol. Med. 3, 701712
(2011).
39. Porrello, E.R. etal. Transient regenerative
potential of the neonatal mouse heart. Science
331, 10781080 (2011).
40. Porrello, E.R. etal. miR15 family regulates
postnatal mitotic arrest of cardiomyocytes.
Circ.Res. 109, 670679 (2011).
41. Porrello, E.R. etal. Regulation of neonatal and
adult mammalian heart regeneration by the
miR15 family. Proc. Natl Acad. Sci. USA 110,
187192 (2013).
42. Eulalio, A. etal. Functional screening identifies
miRNAs inducing cardiac regeneration. Nature
492, 376381 (2012).
43. Liu, N. etal. MicroRNA133a regulates
cardiomyocyte proliferation and suppresses
smooth muscle gene expression in the heart.
Genes Dev. 22, 32423254 (2008).
44. Yin, V.P., Lepilina, A., Smith, A. & Poss, K.D.
Regulation of zebrafish heart regeneration by
miR133. Dev. Biol. 365, 319327 (2012).
45. Chen, J. etal. miR1792 cluster is required
forand sufficient to induce cardiomyocyte
proliferation in postnatal and adult hearts.
Circ.Res. 112, 15571566 (2013).
46. Danielson, L.S. etal. Cardiovascular
dysregulation of miR1792 causes a lethal
hypertrophic cardiomyopathy and
arrhythmogenesis. FASEB J. 27, 14601467
(2013).
47. Bonauer, A. etal. MicroRNA92a controls
angiogenesis and functional recovery of ischemic
tissues in mice. Science 324, 17101713
(2009).
48. Iaconetti, C. etal. Inhibition of miR92a increases
endothelial proliferation and migrationinvitro
aswell as reduces neointimalproliferation
invivo after vascular injury. Basic Res. Cardiol.
107, 114 (2012).
49. Urbich, C., Walter, D.H., Zeiher, A.M. &
Dimmeler,S. Laminar shear stress upregulates
integrin expression: role in endothelial cell
adhesion and apoptosis. Circ. Res. 87, 683689
(2000).
50. Wu, W. etal. Flow-dependent regulation of
Krppel-like factor2 is mediated by
microRNA92a. Circulation 124, 633641
(2011).
51. Doebele, C. etal. Members of the
microRNA1792 cluster exhibit a cell-intrinsic
antiangiogenic function in endothelial cells.
Blood 115, 49444950 (2010).
52. Pin, A.L. etal. miR20a represses endothelial
cell migration by targeting MKK3 and inhibiting
p38 MAP kinase activation in response to VEGF.
Angiogenesis 15, 593608 (2012).
53. Suarez, Y. etal. Dicer-dependent endothelial
microRNAs are necessary for postnatal
angiogenesis. Proc. Natl Acad. Sci. USA 105,
1408214087 (2008).
54. Semo, J. etal. The 106b~25 microRNA cluster
isessential for neovascularization after hindlimb
ischaemia in mice. Eur. Heart J. http://dx.doi.org/
10.1093/eurheartj/eht041.
55. Icli, B. etal. MicroRNA26a regulates
pathological and physiological angiogenesis by
targeting BMP/SMAD1 signaling. Circ. Res. 113,
12311241 (2013).
56. Yin, K.J. etal. Vascular endothelial cell-specific
microRNA15a inhibits angiogenesis in hindlimb
ischemia. J. Biol. Chem. 287, 2705527064
(2012).
57. Spinetti, G. etal. MicroRNA15a and
microRNA16 impair human circulating
proangiogenic cell functions and are increased
in the proangiogenic cells and serum of

NATURE REVIEWS | CARDIOLOGY

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

patientswith critical limb ischemia. Circ. Res.

112, 335346 (2013).
Fasanaro, P. etal. MicroRNA210 modulates
endothelial cell response to hypoxia and
inhibits the receptor tyrosine kinase ligand
ephrinA3. J. Biol. Chem. 283, 1587815883
(2008).
Matsa, E., Sallam, K. & Wu, J.C. Cardiac
stemcell biology: glimpse of the past, present,
and future. Circ. Res. 114, 2127 (2014).
Dimmeler, S., Ding, S., Rando, T.A.
&Trounson,A. Translational strategies and
challenges in regenerative medicine. Nat. Med.
20, 814821 (2014).
Jakob, P. etal. Loss of angiomiR126 and 130a
in angiogenic early outgrowth cells from
patients with chronic heart failure: role for
impaired in vivo neovascularization and cardiac
repair capacity. Circulation 126, 29622975
(2012).
Jansen, F. etal. Endothelial microparticle
mediated transfer of microRNA126 promotes
vascular endothelial cell repair via SPRED1 and
is abrogated in glucose-damaged endothelial
microparticles. Circulation 128, 20262038
(2013).
Chen, J.J. & Zhou, S.H. Mesenchymal stem
cells overexpressing miR126 enhance
ischemic angiogenesis via the AKT/ERKrelatedpathway. Cardiol. J. 18, 675681
(2011).
Huang, F. etal. Mesenchymal stem cells
modified with miR126 release angiogenic
factors and activate Notch ligand Delta-like4,
enhancing ischemic angiogenesis and
cellsurvival. Int. J. Mol. Med. 31, 484492
(2013).
Liu, J. etal. MicroRNA155 prevents necrotic
celldeath in human cardiomyocyte progenitor
cells via targeting RIP1. J. Cell. Mol. Med. 15,
14741482 (2011).
Xu, Q. etal. MicroRNA34a contributes to the
impaired function of bone marrow-derived
mononuclear cells from patients with
cardiovascular disease. J. Am. Coll. Cardiol. 59,
21072117 (2012).
Hu, S. etal. Novel MicroRNA prosurvival
cocktailfor improving engraftment and function
of cardiac progenitor cell transplantation.
Circulation 124 (Suppl.), S27S34 (2011).
Heinrich, E.M. & Dimmeler, S. MicroRNAs
andstem cells: control of pluripotency,
reprogramming, and lineage commitment.
Circ.Res. 110, 10141022 (2012).
Jayawardena, T.M. etal. MicroRNA-mediated in
vitro and in vivo direct reprogramming of cardiac
fibroblasts to cardiomyocytes. Circ. Res. 110,
14651473 (2012).
Nam, Y.J. etal. Reprogramming of human
fibroblasts toward a cardiac fate. Proc. Natl Acad.
Sci. USA 110, 55885593 (2013).
Jayawardena, T.M. etal. MicroRNA induced
cardiac reprogramming in vivo: evidence for
mature cardiac myocaytes and improved cardiac
function. Circ. Res. http://dx.doi.org/10.1161/
CIRCRESAHA.116.304510.
Qian, L. etal. Invivo reprogramming of
murinecardiac fibroblasts into induced
cardiomyocytes. Nature 485, 593598 (2012).
Boon, R.A. & Vickers, K.C. Intercellular
transport of microRNAs. Arterioscler. Thromb.
Vasc. Biol. 33, 186192 (2013).
Hosoda, T. etal. Human cardiac stem cell
differentiation is regulated by a mircrine
mechanism. Circulation 123, 12871296
(2011).
Hergenreider, E. etal. Atheroprotective
communication between endothelial cells and

VOLUME 12 | MARCH 2015 | 141

2015 Macmillan Publishers Limited. All rights reserved

REVIEWS

76.

77.

78.

79.

80.

81.

82.

smooth muscle cells through miRNAs. Nat. Cell

Biol. 14, 249256 (2012).
Zhou, J. etal. Regulation of vascular smooth
muscle cell turnover by endothelial cell-secreted
microRNA126: role of shear stress. Circ. Res.
113, 4051 (2013).
Losordo, D.W. etal. Intramyocardial, autologous
CD34+ cell therapy for refractory angina. Circ. Res.
109, 428436 (2011).
Mocharla, P. etal. AngiomiR126 expression
andsecretion from circulating CD34+ and
CD14+ PBMCs: role for proangiogenic effects
and alterations in type2 diabetics. Blood 121,
226236 (2013).
Barile, L. etal. Extracellular vesicles from human
cardiac progenitor cells inhibit cardiomyocyte
apoptosis and improve cardiac function after
myocardial infarction. Cardiovasc.Res. 103,
530541 (2014).
Ong, S.G. etal. Cross talk of combined gene
and cell therapy in ischemic heart disease:
roleof exosomal microRNA transfer. Circulation
130 (Suppl.1), S60S69 (2014).
Katare, R. etal. Transplantation of human
pericyte progenitor cells improves the repair of
infarcted heart through activation of an
angiogenic program involving microRNA132.
Circ. Res. 109, 894906 (2011).
Ibrahim, A.G.E., Cheng, K. & Marbn, E.
Exosomes as critical agents of cardiac

142 | MARCH 2015 | VOLUME 12

83.

84.

85.

86.

87.

88.

89.

regeneration triggered by cell therapy. Stem Cell

Reports 2, 606619 (2014).
Cheng, H.S. etal. MicroRNA-146 represses
endothelial activation by inhibiting proinflammatory pathways. EMBO Mol. Med. 5,
949966 (2013).
Chen, L. etal. Cardiac progenitor-derived
exosomes protect ischemic myocardium
fromacute ischemia/reperfusion injury.
Biochem. Biophys. Res. Comm. 431, 566571
(2013).
Yu, B. etal. Cardiomyocyte protection by
GATA4gene engineered mesenchymal stem
cells is partially mediated by translocation of
miR221 inmicrovesicles. PLoS ONE 8, e73304
(2013).
Bang, C. etal. Cardiac fibroblastderived
microRNA passenger strand-enriched exosomes
mediate cardiomyocyte hypertrophy. J. Clin. Invest.
124, 21362146 (2014).
Bellera, N. etal. Single intracoronary injection
ofencapsulated antagomir92a promotes
angiogenesis and prevents adverse infarct
remodeling. J. Am. Heart Assoc. 3, e000946
(2014).
van Rooij, E. & Kauppinen, S. Development
ofmicroRNA therapeutics is coming of age.
EMBO Mol. Med. 6, 851864 (2014).
Kota, J. etal. Therapeutic microRNA delivery
suppresses tumorigenesis in a murine

90.

91.

92.

93.

livercancer model. Cell 137, 10051017

(2009).
US National Library of Medicine. ClinicalTrial.gov
[online], http://clinicaltrials.gov/ct2/show/
NCT01829971 (2014).
Bonci, D. etal. The miR15amiR161 cluster
controls prostate cancer by targeting multiple
oncogenic activities. Nat. Med. 14, 12711277
(2008).
Schfer, F., Wagner, J., Knau, A., Dimmeler, S.
&Heckel, A. Regulating angiogenesis with lightinducible antimiRs. Angew. Chem. Int. Ed. Engl.
52, 1355813561 (2013).
Bish, L.T. etal. Adeno-associated virus (AAV)
serotype9 provides global cardiac gene transfer
superior to AAV1, AAV6, AAV7, and AAV8 in the
mouse and rat. Hum. Gene Ther. 19, 13591368
(2008).

Acknowledgements
The authors are funded by the German Center for
Cardiovascular Research DZHK (BMBF), the LOEWE
Center for Cell and Gene Therapy (State of Hessen), the
Deutsche Forschungsgemeinschaft (SFB834), and
theFondation Leducq Transatlantic Network MIRVAD.
Author contributions
Both authors researched data for the article,
discussed its content, and wrote, reviewed, and
edited the manuscript before submission.

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