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ATVB in Focus
MicroRNAs: From Basic Mechanisms to Clinical
Application in Cardiovascular Medicine
Series Editor: Christian Weber
MicroRNAs in Stem Cell Function and Regenerative
Therapy of the Heart
Florian H. Seeger, Andreas M. Zeiher, Stefanie Dimmeler
Abstract—MicroRNAs are small noncoding RNAs that posttranscriptionally control gene expression by targeting mRNAs.
Distinct microRNAs regulate stem and progenitor cell functions, thereby modulating cell survival and homing or
controlling differentiation and maturation. Experimental studies additionally show that microRNAs regulate endogenous
repair and might potentially be useful to enhance the regeneration of the heart. This review summarizes the current studies
that address the use of microRNAs to either improve cellular therapies or that might be targeted for enhancing endogenous
tissue repair and regeneration after myocardial infarction. (Arterioscler Thromb Vasc Biol. 2013;33:1739-1746.)
Key Words: cardiac repair ◼ miR ◼ microRNA ◼ regenerative therapy ◼ stem cell function
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C
oronary artery disease is a progressive disease with a high
morbidity and mortality worldwide. Despite improved
primary prevention, as well as interventional and pharmacological therapies, the incidence of heart disease is further
increasing particularly because of metabolic disorders and
an extended life span. After an acute myocardial infarction,
the death of cardiomyocytes, which cannot sufficiently be
replaced by endogenous regeneration, renders the heart susceptible for unfavorable remodeling and heart failure. Stem/
progenitor cell therapies have been considered as promising
options to compensate for the loss of cardiomyocytes. Various
adult stem/progenitor cells were used in experimental and
clinical trials,1,2 and bone marrow–derived proangiogenic cells
and mesenchymal stromal cells were shown to augment the
recovery after ischemia in experimental models. The clinical
trials overall showed a modest improvement in heart function3,4; however, the results had been heterogeneous and larger
scale trials are ongoing to test whether cell therapy with bone
marrow–derived cells indeed can improve patient survival. In
addition, cardiac stem cells recently showed promising results
in phase I/II clinical trials.5,6 Embryonic or induced pluripotent
stem cells so far have shown the highest capacity to replace
dead myocardium; however, their clinical use is hampered by
potential safety hurdles that first need to be addressed.7
and Dicer, and the mature miRNAs are incorporated into the
RNA-inducing silencing complex to target mRNAs. About
2000 miRNAs have been identified in humans, and miRNAs
are known to influence the expression of ≈30% of the genes.
miRNAs contribute to embryonic development and tissue
homeostasis but even more profoundly regulate pathophysiological processes.9–11 Tissue injury, as for example myocardial
infarction, profoundly disturbs the expression of miRNAs.12
MiRNAs also have an important influence on stem cells; several miRNA families were shown to be required to maintain
pluripotency of embryonic stem cells,13,14 and recent studies
demonstrated that the combined overexpression of miRNAs
is sufficient to induce pluripotent stem cells.13,14 Although the
downregulation of pluripotency-related miRNAs is required
for differentiation, the differentiation and maturation of stem
cells are associated with the increased expression of lineageenriched miRNAs.13,14 Finally, stem/progenitor cell functions
are controlled by miRNAs.13 Here, we review the current studies that address the use of miRNAs to either improve cellular
therapies or that might be targeted for enhancing endogenous
tissue repair and regeneration after myocardial infarction.
MiRNAs for Cell Enhancement
Various adult progenitor cells, embryonic stem cells, or
reprogrammed cells were successfully used to augment heart
function after ischemia.1 However, the experience in clinical
trials and longer term follow-up studies in experimental
models revealed several major challenges: (1) particularly,
bone marrow–derived cells showed an impairment in function
and survival when isolated from aged patients with chronic
disease; (2) the homing and long-term integration of cells
applied was poor in most studies15; and (3) a direct cardiac
regeneration by replacement of cardiomyocytes was modest or
absent in the majority of studies testing adult progenitor cell
This article accompanies the ATVB in Focus:
MicroRNAs: From Basic Mechanisms to Clinical
Application in Cardiovascular Medicine series
that was published in the February 2013 issue.
MicroRNAs (miRNAs/miRs) are small noncoding RNAs
that control gene expression by binding to target mRNAs and
thereby inducing translational repression or mRNA degradation.8 MiRNAs are processed by several maturation steps
mediated by protein complexes, including the RNases Drosha
Received on: February 15, 2013; final version accepted on: April 25, 2013.
From the Department of Cardiology, Internal Medicine III (F.H.S., A.M.Z.) and Institute for Cardiovascular Regeneration, Centre of Molecular Medicine
(S.D.), Goethe University Frankfurt, Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, PhD, Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, TheodorStern-Kai 7, 60590 Frankfurt, Germany. E-mail [email protected]
© 2013 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
1739
DOI: 10.1161/ATVBAHA.113.300138
1740 Arterioscler Thromb Vasc Biol August 2013
populations so far.16 Therefore, several attempts were made to
improve cell therapy by interfering with cell function, homing,
survival, or differentiation.15 Because miRNAs change gene
expression networks and can be easily inhibited by small
molecules, they might be interesting candidates to ex vivo treat
cells before transplantation. Various miRNAs are modulated
by cardiovascular risk factors and disease, and reversal of the
deregulated miRNAs might improve the functional capacity of
cells in patients with coronary artery disease17–20 (Figure 1).
Improvement of Cell Survival
and Function by MiRNAs
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Cell survival was affected by several miRNA families in adult
progenitor cells or proangiogenic cells. For example, miR-126
was used to augment the efficiency of transplanted cells. miR126 was initially shown to be essential for angiogenic signaling
in endothelial cells, but also improved cell survival and migration of mesenchymal stromal cells (MSCs) and proangiogenic
bone marrow–derived cells.17,21–23 This may be particularly
relevant for autologous cells because both, diabetes mellitus
and heart failure, were shown to downregulate miR-126 levels in patient-derived cells.17,19,24 Ex vivo overexpression of
miR-126 in MSC or proangiogenic cells improved angiogenesis and augmented the recovery in experimental myocardial
infarction models.22,23 MiR-126 is known to repress inhibitors
of the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway,
which results in the activation of the prosurvival Akt signaling
pathway, which promotes cell survival and might also enhance
the release of paracrine factors as previously reported for Aktoverexpressing MSC.25 Indeed, Huang et al23 showed that
overexpression of miR-126 augments the release of paracrine
factors from MSC, which contributes to the improvement of
repair after cell transplantation. Besides Akt, miR-126 controls the expression of the Notch ligand Delta-like 4 in MSC.
By controlling this pathway, miR-126 does not only improve
cell survival but also promotes tubulogenesis.23
Interestingly, miR-126 seems not only to act as cell intrinsic regulator of cell functionality but is also released and acts
in a paracrine manner to augment neovascularization. The
cellular release of exosomes, which among other factors contain miRNAs, is known to mediate cell-to-cell communication between several cell types.26–28 For example, exosomes
derived from CD34+ cells improve neovascularization after
ischemia.29 A recent study now demonstrates that miR-126
is preferentially enriched in microvesicles derived from
CD34+ cells compared with other cell types and contributes to the proangiogenic activity of the cell supernatants.19
In addition, Cantaluppi et al30 demonstrated that proangiogenic cells release miRNAs 126– and miR-296–containing
microvesicles that induce angiogenesis in endothelial cells.
An impaired expression of miR-126 was demonstrated in
microvesicles isolated from supernatants of peripheral blood
CD34+ cells from patients with diabetes mellitus, and overexpression of miR-126 restored the proangiogenic activity of
diabetic CD34+ cells.19 These findings are consistent with the
lower circulating levels of miR-126 detected in patients with
diabetes mellitus or coronary artery disease31,32 and overall
may contribute to the known impaired neovascularization
capacity observed in patients with diabetes mellitus.
MiR-34a represents a second example that is regulated during disease and affects the functional capacity and survival of
cells used for cell therapy. miR-34a is profoundly induced by
aging and in bone marrow–derived cells from patients with
heart failure and its inhibition improved the survival of the cells
in vitro.20 Ex vivo treatment of bone marrow–derived mononuclear cells with miR-34a inhibitors augments the cell transplantation–induced improved functional recovery after acute
myocardial infarction.20 Vice versa, overexpression of miR-34a
induced cells death20 and worsened the proangiogenic activity
of proanigogenic cells by increasing senescence.33 In addition,
miR-34a influenced apoptosis signaling by, for example, targeting the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and it
blocked cellular proliferation by repression of cell cycle regulators, such as cyclin D2 and cyclin-dependent kinases.20,34 In
proangiogenic cells the histone deacetylase silent mating type
information regulation 2 homolog 1 (SIRT1) was reported to be
inhibited by miR-34a, which may additionally contribute to the
detrimental function of miR-34a in vascular repair.35,36
MiRNAs also augmented cell survival and in vivo functional
capacity of cardiac stem/progenitor cells. An interesting study
tests the effect of individual miRNAs versus combinations and
showed that the combination of 3 miRNAs, namely miR-21,
miR-24, and miR-221, is more efficient to improve engraftment
and survival of transplanted cardiac progenitor cells.37 The
above-mentioned miRNAs target the apoptotic protein Bim and
thereby directly improve cell survival.37 In addition, miR-155
overexpression repressed necrosis of cardiac stem cells.38
Cellular senescence, which compromises cellular functions, can be regulated by miRNAs. Thus, miR-10a*, miR21, and miR-34a increase senescence of proangiogenic cells,
whereas the inhibition of these miRs improved angiogenesis.33,36,39 Particularly, antagonizing miR-21 reduced reactive
oxygen species production,18 which can contribute to cellular
dysfunction and senescence.
Several miRNAs modulated the migration of cells; miR-150
and miR-146 target the stromal cell-derived factor 1 (SDF-1)
receptor chemokine receptor type 4 (CXCR4), which is essential for progenitor and proangiogenic cell homing to ischemic
tissues,40,41 and miR-15a and miR-16 were recently shown to
profoundly inhibit the migratory potential of proangiogenic
cells isolated from patients with critical limb ischemia.42 The
targets of miR-15a/16 include the proangiogenic cytokine vascular endothelial growth factor (VEGF) and the Akt isoform-3
that contribute to the defective function of proangiogenic cells
from patients with limb ischemia.42 However, both miRNAs
target a variety of antiapoptotic proteins that may have contributed to their detrimental effects as well.
Enhancement of Differentiation of
Transplanted Stem/Progenitor Cells
Although embryonic stem cells can acquire a cardiac muscle
cell phenotype and, therefore, might be useful to regeneration
therapies, their integration, survival, and homing have been shown
to be limited in some studies.43 Moreover, the generation of fully
mature differentiated cells is a major challenge. Recent studies
Seeger et al MicroRNAs and Cardiac Repair 1741
now suggest that overexpression of miR-1 in embryonic stem
cells enhanced cardiac differentiation after transplantation,44,45 a
finding which is consistent with previous in vitro reports showing
an increase in cardiac lineage commitment by the overexpression
of cardiac miRs, such as miR-1 or miR-499.46–48 Whether
such an approach might be also useful to improve the cardiac
differentiation capacities of adult progenitor cells deserves further
studies. Interestingly, the miR-1–overexpressing embryonic
stem cells also reduced apoptosis of the host cardiomyocytes
suggesting that miRNAs can exhibit pleiotropic effects, which
together may lead to a better tissue repair.
In summary, ex vivo regulation of several miRNAs by antimiRs or miR mimics can improve cell survival and affects
the functions of several stem/progenitor cells and proangiogenic cells that are used for therapeutic augmenting cardiac
repair and regeneration. The engineering of cells by ex vivo
treatment with anti-miR mimics might be a promising tool to
improve the success of cell therapy.
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MiRNAs and Postischemic Protection
The recovery of heart function after ischemia is influenced
by various processes and can be enhanced by blocking cardiomyocyte cell death or by improving tissue perfusion. In
addition, the invasion of inflammatory cells enhances tissue
damage; however, inflammation is also required for wound
healing and tissue remodeling. During later stages, the replacement of dead cardiomyocytes by fibrotic tissue contributes to
the impairment of heart function. Given the multiple functions
of miRNAs, it does not come as a surprise that all of these
processes are regulated by diverse miRNAs.
Prevention of Cardiomyocyte Death
The miR-15 family, which comprises 6 closely related miRs, is
increased in murine and pig hearts within 24 hours after ischemia/reperfusion injury.49 Inhibition of miR-15 family members
reduced hypoxia and hypoxia/reoxygenation-induced cardiomyocyte cell death49 and improved mitochondrial function and
ATP levels.50 In vivo, miR-15 inhibition by short locked nucleic
acid-based anti-miRs (so called tiny miRs) reduces infarct size
in mice after ischemia/reperfusion injury.49 MiR-15 targets the
antiapoptotic protein Bcl-2 and the mitochondrial protective
protein ADP-ribosylation factor-like 2 in cardiomyocytes.49,50
A similar effect was reported for the miR-34 family, which
is induced by myocardial infarction and promotes cardiomyocyte cell death.51–53 Inhibition of miR-34 family members
improved cardiac function after acute myocardial infarction.53,54
Moreover, a cardioprotective effect was observed during cardiac aging.54 MiR-34a targets SIRT1, which is a vasculo- and
cardioprotective deacetylase, and its derepression contributes to
the antiapoptotic effects of miR-34 inhibition. In addition, the
protein phosphatase 1 regulator PNUTS (or serine/threonineprotein phosphatase 1 regulatory subunit 10 [PPP1R10]), a
protein involved in DNA damage response and telomere shortening, is repressed by miR-34 (Figures 1 and 2).52,54
Among the miRNAs that are upregulated after cardiac stress,
miR-214 exhibits a protective function. miR-214 is downregulated during embryonic development and further decreased in
adult mice, but it is reexpressed within 7 days after ischemia/
reperfusion injury.55 Genetic deletion of miR-214 aggravated
ischemic/reperfusion-induced cell death and induced a further
deterioration of heart function.55 This effect was at least in part
mediated by a repression of the sodium/calcium exchanger
Ncx1, which under stress conditions contributes to calcium
overload.55 Three miR-214 targets, namely cyclophilin D—a
regulator of the mitochondrial permeability transition pore—
the proapoptotic protein Bim, and the hypertrophy-regulating
Ca2+/calmodulin-dependent protein kinases I (CaMKIId),
were identified in the hearts and all may contribute to the
observed protective effect of this miRNA.55
The proapoptotic protein Bim is additionally targeted
by miR-24, which is downregulated after acute myocardial
infarction.56 Overexpression of miR-24 reduced cardiomyocyte apoptosis in vitro and in vivo and attenuated infarct size
and improved heart function after myocardial infarction.56
Moreover, miR-20a, which is part of the miR17-92 cluster,
inhibits apoptosis of cardiomyocytes.57
Improvement of Perfusion/Angiogenesis
MiR-92a was the first miRNA shown to control neovascularization after acute myocardial infarction.58 Inhibition of
miR-92a enhanced endothelial cell migration and sprouting
in cell culture studies.58,59 In vivo, miR-92a is increased within
the first days after infarction and its inhibition increased capillary density and improved heart function after myocardial
infarction.58 In endothelial cells, miR-92a targets integrin a5,58
which prevents endothelial cell apoptosis and is important
for vessel maturation.60 In addition, several vasculoprotective
genes were repressed by miR-92a, such as SIRT1, which prevent endothelial NO synthase acetylation and inactivation.61
In addition, various miRNAs are meanwhile identified as
regulators of angiogenesis.62 Most studies, however, did not
test the function in myocardial infarction. Among the miRNAs
that are tested for their potential role in regulating cardiac
neovascularization, miR-24 was shown to inhibit angiogenesis in various models, and antagomirs directed against miR24 improved the recovery after acute myocardial infarction
by targeting the endothelium-enriched transcription factor
GATA2 and the p21-activated kinase 4.63 The improvement
of cardiac function by antagomirs directed against miR-24
is counterintuitive to the above-discussed findings that miR24 overexpression attenuates infarct size and improved heart
function.56 However, recent studies showed that antagomirs
directed against miR-24 protected against the transition from
hypertrophy to decompensated heart failure by interfering with
excitation–contraction coupling after aortic constriction.64
Further studies need to clarify the role of miR-24 in neovascularization versus direct cardioprotection. One may speculate that the inhibitors target different cells and affect different
pathways compared with the unphysiological overexpression
of the miRNA.
The miR-15 family inhibits angiogenesis after hind-limb
or myocardial ischemia,49,65,66 which in combination with the
induction of cardiac cell death may contribute to the profound
functional effects of miR-15 inhibitors in experimental myocardial infarction discussed above.
1742 Arterioscler Thromb Vasc Biol August 2013
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Figure 1. Effects of microRNAs (miRNAs/miRs) on
cell therapy. The figure summarizes the possible
use of miRNAs to improve for cell therapy (A) and
shows some of the mechanisms by which miRNAs
regulate the function of proangiogenic cells for
cardiovascular repair (B). BIM indicates B-cell lymphoma 2 interacting mediator of cell death; CDK,
cyclin dependent kinase; and Dll, delta-like protein.
Prevention of Fibrosis
MiR-29 is repressed by cardiac stressors, such as
aortic banding, and is reduced after acute myocardial
infarction.12,67 Interestingly, the miR-29 family targets
multiple proteins involved in fibrosis, including multiple
collagens, fibrillins, and elastin.12,68 Thus, overexpression
of miR-29 might be an interesting therapeutic option to
block the fibrotic response.
MiR-21 was among the first miRNAs that was shown to
be upregulated after acute myocardial infarction.12 Subsequent
studies blocked miR-21 by antagomirs and reported that this
enhanced cardiac function and prevents cardiac fibrosis.69
However, genetic deletion of miR-21 or blocking of miR-21
with shorter locked nucleic acid-based anti-miRs had no effect
in other studies.70 Although ample evidence supports a direct
profibrotic function of miR-21,71 it might have additional
functions in other cells. For examples, miR-21 was shown to
prevent H2O2-induced cardiomyocyte cell death.72 Likewise,
overexpression of miR-21 via adenovirus-expressing miR21 inhibited cardiomyocyte apoptosis and decreased myocardial infarct size after acute myocardial infarction.73 These
studies showed that miR-21 targets the proapoptotic gene–
programmed cell death 4 and the activator protein 1 pathway,
which play a crucial role in cardiomyocyte cell death.74
MiR-101 has also been implicated in cardiac fibrosis. It is
downregulated after 4 weeks of acute myocardial infarction
and forced overexpression of miR-101a/b, to compensate for
the long-term repression of this miR, inhibited proliferation
of cardiac fibroblasts, and reduced collagen production.75
Mechanistically, miR-101 was targeting the c-fos and transforming growth factor-β1 signaling pathways.75
MiRNAs and Endogenous Cardiac
Regeneration
Attempts to truly regenerate the heart have been challenging
particularly because the strategy of exogenous cell therapy
faced multiple problems, including the limited survival, integration, and differentiation capacity of various tested cell
types.15,76 Although the adult mammalian heart is one of the
least regenerative organs, recent studies suggest that activation of endogenous cardiac regeneration might be possible by
Seeger et al MicroRNAs and Cardiac Repair 1743
Cardiomyocyte
proliferation
Cell death
miR-15
miR-195
miR-199
miR-590
miR-15
miR-24
miR-34
miR-214
(calcium
overload)
Cardiac reprogramming
Fibrosis
miR-21
miR-29
miR-101
Angiogenesis
miR-15
miR-24
miR-92a
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augmenting cardiomyocyte proliferation or by reprogramming
fibroblasts into functional cardiomyocytes. MiRNAs might be
suitable to trigger or enhance both processes.9,77 Moreover,
a combination of miRNAs can be used to turn fibroblasts to
induced pluripotent stem cells.13
MiRNAs and Cardiomyocyte Proliferation
MiRNA expression profiles in neonatal mouse hearts, which
possess the capacity to regenerate at least until day 7, showed
that several miRNAs are regulated during postnatal cardiac
development. Among the highly regulated miRNAs are members of the miR-15 family, particularly miR-195, which is
upregulated within the first days after birth.78,79 The miR-195
upregulation coincides with the postnatal transition of the heart
toward cell cycle arrest, suggesting that it might contribute to
the mitotic arrest of cardiomyocytes after birth. Indeed, inhibition of miR-15 family members increased the rate of proliferating cardiomyocytes up to day 12 after birth,78 whereas
overexpression of miR-195 impaired cardiomyocyte proliferation and induced ventricular hypoplasia and septal defects.78
The miR-15 family members profoundly modulated the expression of proliferation-associated genes in cardiomyocytes, a
finding that is consistent with the antiproliferative activity of
miR-15 in other cell types.80 Specifically, checkpoint kinase 1
was identified as a direct target of miR-15 in cardiomyocytes.78
A functional miRNA screen recently confirmed that miR-15
inhibits cardiomyocyte proliferation.81 Furthermore, various
additional miRNAs were identified that control cardiomyocyte proliferation. Two of these miRNAs, namely miR-590
and miR-199a, were further validated and the study shows that
overexpression of each of these miRNAs promotes cardiomyocyte proliferation in neonatal and adult mice.81 Interestingly,
viral overexpression of the miRNAs enhanced cardiomyocyte
proliferation and preserved long-term cardiac function after
permanent ligation of the coronary artery.81 Together, at least
in mouse models, miRNAs may be useful to reverse the cell
cycle blockade of adult cardiomyocytes. Further studies have
to evaluate the function in adult human cardiomyocytes.
Fibroblast
miRNAs?
Figure 2. MicroRNAs (MiRNAs) in postinfarction repair.
miR-1
miR-208
miR-499
Induced
Cardiomyocyte
MiRNAs and Direct Reprogramming
Besides inducing cardiomyocyte proliferation, miRNAs may
be also useful to augment direct cardiac reprogramming.
Direct cardiac reprogramming of fibroblasts has first been
achieved by combined overexpression of cardiac transcription
factors, such as GATA4, myocyte-specific enhancer factor 2C
(MEF2C), and T-box transcription factor (TBX5),82,83 or the 3
factors with the addition of Hand2.84 As discussed above, cardiac-enriched miRNAs were shown to facilitate cardiac differentiation of stem cells.44,46,47,85 Therefore, Jayawardena et al86
tested whether miRNAs might be helpful to convert fibroblasts
into cardiomyocyte-like cells. Indeed, the combination of several miRNAs, namely miR-1, miR-133, miR-208, and miR499, augmented cardiac marker gene expression in fibroblasts
in vitro. Overexpression of the miR cocktail also increased the
reprogramming of cardiac fibroblasts into cardiomyocytes in
vivo as shown by using lineage tracing.86 Although the extent
of converting fibroblasts into cardiomyocytes in principle is
rather low and even more challenging in human cells, further
studies may overcome these hurdles by combining transcription factors with miRNAs and small molecules to optimize
this promising therapeutic strategy.
Outlook
Various experimental studies provide convincing evidence
that miRNAs might be targeted to improving cell therapy
or enhancing endogenous repair processes. Despite these
encouraging data, the development of miRNA therapeutics
faces several challenges and questions; although miRNA
inhibition is very efficient,87 overexpression of miRNAs is not
yet established with small molecules and requires the use of
vectors. Gene therapy recently gained back attention with the
first gene therapy being approved in Europe88 and promising
results being reported for cardiac gene therapy with the adenoassociated virus-vectors89; however, it is still not at a stage that
would allow easy clinical translation. Second, the biology
of miRNAs is far from being understood and the moderate
repression of multiple targets by miRNAs requires a system
1744 Arterioscler Thromb Vasc Biol August 2013
biology approach to identify the full impact on the gene
expression networks. Some miRNAs target patterns of genes
with a common biological function (eg, miR-29 targeting
various matrix proteins); however, other miRNAs target
genes with antagonistic functions (eg, pro- and antiapoptotic
genes) making it even more complicated to understand the
biological activities. Finally, targeting ubiquitously expressed
miRNAs may face challenges with respect to unwanted side
effects in other cells or tissue. Therefore, cell type–specific
delivery strategies may be required in some cases. However,
the promising results from recent phase II clinical trials
documenting not only the safety and feasibility but also the
biological function of anti-miRs for the treatment of hepatitis
encourage the development of miRNA therapeutics for the
treatment of cardiovascular diseases.
Acknowledgments
We thank Susanne Heydt for the artwork.
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Disclosures
S. Dimmeler is supported by the European Research Council advance
grant Angiomir. S. Dimmeler and A.M. Zeiher are founders of t2cure
GmbH. The other author reports no conflicts.
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MicroRNAs in Stem Cell Function and Regenerative Therapy of the Heart
Florian H. Seeger, Andreas M. Zeiher and Stefanie Dimmeler
Arterioscler Thromb Vasc Biol. 2013;33:1739-1746
doi: 10.1161/ATVBAHA.113.300138
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