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Rupture of Vulnerable Atherosclerotic Plaques: MicroRNAs Conducting the


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Article  in  Trends in cardiovascular medicine · February 2010


DOI: 10.1016/j.tcm.2010.04.002 · Source: PubMed

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be performed at different levels, such
Rupture of Vulnerable Atherosclerotic as for instance proteomics, lipidomics,
Plaques: MicroRNAs Conducting or RNA analysis. With respect to RNA
analysis, the discovery of microRNAs
the Orchestra? (miRNAs) may yield new diagnostic
and 1even therapeutic options. Recent
Vincent G. Haver, Riemer H.J.A. Slart, Clark J. Zeebregts, studies suggest a role for miRNAs in
Maikel P. Peppelenbosch, and René A. Tio⁎ cardiovascular disease and atherosclero-
sis (Blake and Ridker 2001, Dong et al.
2009, Ji et al. 2007, Scalbert and Bril 2008,
Zhang 2009).
MicroRNAs (miRNAs) are tiny, endogenous nucleotides that bind to
Many genetic risk factors for athero-
mRNA and induce translation repression within metazoan cells. Since sclerosis and restenosis have been iden-
their discovery in 1993 in Caenorhabditis elegans and the demonstra- tified (e.g., Monraats et al. 2010). After
tion of miRNAs in Homo sapiens in 2000, research has been fruitful in transcription of genomic DNA, transla-
deciphering the role of these nucleotides in development, tissue tion of RNA (mRNA) will yield the gene
product—a protein. Interestingly, less
homeostasis, and pathologic processes. In humans, around 700 human than 20 years ago, it has been shown
miRNA nucleotides have been verified, which interfere with 30% of all that miRNAs are important players in
genes. Recently, the role of miRNA in cardiovascular research gained translational control of mRNA before
attention and the involvement of miRNAs in several cardiovascular translation takes place. They are short,
noncoding RNA molecules that inter-
diseases has been identified. In this review, we focus on the role of
fere with mRNA, thereby, inducing
miRNAs in atherosclerosis and in particular on the potential role of translational repression (Mishra et al.
miRNAs in the development of vulnerable atherosclerotic plaques. The 2009). They can act as important
role of miRNA in the main characteristics of these plaques, inflamma- regulators in inflammation as well as
tion, angiogenesis, and apoptosis will be discussed. Finally, the future angiogenesis, both important character-
istics of plaque vulnerability. After their
perspectives and miRNA-based diagnostic and therapeutic potentials first identification in the nematode
will be highlighted. (Trends Cardiovasc Med 2010;20:65–71) n 2010, Caenorhabditis elegans species, it has
Elsevier Inc. become evident that they are present in
a large variety of other species as well,
 such as worms, mice, and human
Introduction low-density lipoprotein-filled foam cells
(Pasquinelli et al. 2000).
(N40% of the plaque), a thin fibrous cap,
Hundreds of miRNAs have been
Atherosclerosis is one of the leading which is depleted of smooth muscle cells,
identified in vivo or predicted in silico
causes of mortality in the Western world. inflammatory cell infiltration (mainly
from the genomes of plants, worms,
Apart from its anatomical and physiologic macrophages), newly formed vessels (an-
flies, and mammals (MicroRNA.org).
characteristics, the vulnerability or biolo- giogenesis or neovascularization), intra-
Bioinformatic predictions indicate that
gy of a plaque is of the utmost importance plaque hemorrhage, and outward
the mammalian miRNAs can regulate
for its clinical sequelae. Vulnerable pla- remodeling (Hellings et al. 2007). Molec-
approximately 30% of all protein-coding
ques have a large lipid core composed of ular analysis of vulnerable plaques can
genes (Suarez and Sessa 2009). This
number of miRNAs is much higher than
previously expected and indicates the
Vincent G. Haver, Riemer H.J.A. Slart, Clark J. Groningen, Groningen, The Netherlands; importance of these regulatory noncod-
Zeebregts, and René A. Tio are at the and Maikel P. Peppelenbosch at the Depart-
ing RNAs. The number of a specific
Cardiovascular Imaging Group Groningen, ment of Gastro-enterology and Hepatology,
University Medical Center Groningen, Uni- Erasmus Medical Center Rotterdam, The miRNA can differ per cell type and per
versity of Groningen, Groningen, The Netherlands. tissue. In some cells, the number of a
Netherlands; Department of Cardiology, Uni- ⁎ Address correspondence to: René A. Tio, specific miRNA molecule can be as high
versity Medical Center Groningen, University Department of Cardiology, Thorax Center, as 10,000, whereas other miRNAs are
of Groningen, Groningen, The Netherlands; University Medical Center Groningen, Univer- only detectable by hybridization of total
Department of Nuclear Medicine and Molec- sity of Groningen, Hanzeplein 1, 9713GZ
RNA (Ambros 2004).
ular Imaging, University Medical Center Groningen, The Netherlands. Tel.: (+31)
Groningen, University of Groningen, Gronin- 503612355; fax: (+31) 503611347; e-mail: r.a.
The aim of this review was to sum-
gen, The Netherlands; Department of Surgery tio@thorax.umcg.nl. marize the potential role of miRNAs in
division of Vascular Surgery, University © 2010, Elsevier Inc. All rights reserved. atherosclerotic plaque formation and
Medical Center Groningen, University of 1050-1738/$-see front matter plaque rupture. After a short

TCM Vol. 20, No. 2, 2010 65


explanation of miRNA processing and miRNA into double-stranded transient perfect complementary binding of
the role of miRNA in normal develop- duplex miRNA (miRNA and a partially miRNA, target mRNA 3′untranslated
ment, the function of miRNAs in complementary strand, referred to as regions (UTRs) can be cleaved and
pathologic processes related to athero- miRNA*) containing approximately two degraded, but in animals, generally,
sclerotic plaque development and vul- nucleotides 3′ overhangs at both ends. binding is imperfect, and translation is
nerability are discussed. Proteins with double-stranded RNA- repressed without cleavage of mRNA
binding domains (such as TRBP, TAR (Suarez and Sessa 2009). However, it

RNA binding protein and PACT, protein also has been stated that miRNAs in
miRNA Processing
activator of PKR (protein kinase acti- animals lead to considerable cleavage of
miRNA processing is a complex process vated by dsRNA) bind to Dicer and target mRNAs (Jovanovic and Hengart-
F1 (Figure 1) and has been investigated enhance the affinity of Dicer for RNA, ner 2006).
intensely within the past 2 decades thereby, participating in the selection of As mentioned previously, nonperfect
(Suarez and Sessa 2009). miRNAs are mature miRNA strands (Zeng 2006). binding of miRNA leads to translational
either intergenic, polycistronic, or intro- The double-stranded miRNA duplex is suppression of target mRNAs. This impli-
nic. The primary miRNA (pri-miRNA) incorporated into the RNA-induced si- cates that one particular miRNA can
capped, and polyadenylated transcript, lencing complex (RISC), containing pro- regulate hundreds of genes, and one
which can be thousands of nucleotides teins of the Argonaute family (e.g., Ago gene can be regulated by a number of
long, is transcribed within the nucleus 2). Within this RISC complex, the miRNAs (Sen et al. 2009). This indicates
by RNA polymerase III (or II) from any miRNA duplex is unwound into the the major impact of miRNAs in transla-
of the aforementioned encoding regions mature single-stranded form (guide tional control.
of miRNA. Drosha (an RNase III type strand), and its complementary strand
endonuclease) releases the stem loop (miRNA*) is degraded (Suarez and  miRNA Mechanisms
structure resulting in a 70 to 100 Sessa 2009). The miRNA–RISC complex
nucleotide hairpin-shaped precursor regulates the concentration of a partic- Altered miRNA concentrations within a
(pre-miRNA) by cleaving the 5′cap and ular protein in a cell by either degrading cell logically results in a modified level of
polyadenylated tail. Drosha requires a the complimentary mRNA with the use RNA interference. Because miRNA
regulatory subunit called DGCR8 in of the RNAi mechanism or by inhibiting destroys or blocks translation of mRNA,
humans (Zeng 2006). The pre-miRNA the translational machinery of protein up-regulation of miRNA leads to a down
is transported from the nucleus to the dependent on the affinity for mRNA regulation of target protein, whereas a
cytoplasm, where Dicer cleaves pre- molecules. In cases of perfect or near- down regulation of miRNA causes an up-
regulation of the aimed protein.
The mechanisms behind the involve-
ment of miRNA in diseases are not
completely understood. However, some
hypotheses are raised and are shown
below. Probably, multiple mechanisms
are responsible for the changes seen in
diseases. Recently four ways of miRNA
involvement have been proposed (Son-
koly and Pivarcsi 2009).

- Loss or down regulation of


miRNA expression due to mu-
tation, epigenetic inactivation,
aberrant processing, or tran-
scriptional down regulation.
Down regulation is common
in cancer and inflammatory
diseases.
- Overexpression of miRNA due to
gene amplification or mutations
in the promoter region, for ex-
ample, oncomirs (miRNAs in-
volved in the development of
cancer).
- A mutation in the 3′UTR of an
Figure 1. miRNA possessing. After transcription of intronic miRNA by RNA polymerase II, it
takes several steps before the mature miRNA nucleotide is loaded within the RISC complex mRNA may affect a miRNA-
and induces either mRNA degradation or mRNA translational repression. See text for binding site, leading to overex-
further explanation. (Color version of figure is available online.) pression of the target gene.

66 TCM Vol. 20, No. 2, 2010


- A mutation in the 3′UTR of a et al. 2009). This further implies poten- level of vascular endothelial growth
gene generating a new miRNA- tial miRNA-related targets to modulate factor (VEGF) and hypoxia. Blockade of
binding site. plaque development and stability. miR-210 inhibits hypoxia-induced vessel
Recently, it has been shown that formation and is a key player in VEGF-

mature miR-1 and -206 levels were driven endothelial cell migration (Fasa-
miRNAs in Atherosclerosis
significantly up-regulated 1 week after naro et al. 2009). Vascular endothelial
Many miRNAs have been found in heart myocardial infarction induction (Shan growth factor is also a target of miR15b,
and vascular tissue. Of 180 miRNAs et al. 2009). Furthermore, both miRNAs -16, -20a, and -20b, and these miRNAs
arrayed, 140 miRNAs were found in have been related to reduction of insulin- are sharply down regulated after hypox-
carotid arteries in rats (Ji et al. 2007), like growth factor 1. As a result, the ia. Inhibition of these posttranslational
and 157 miRNA of 233 miRNAs extent of apoptosis increased (Shan et al. regulators increased VEGF expression
arrayed were found in mouse hearts 2009, Yu et al. 2008). Interestingly cardi- significantly (Hua et al. 2006) indicating
(Cheng et al. 2007). oprotective miRNA effects have been that miRNAs are part of the angiogenic
Endothelial cells are the first line of shown (miR-21) resulting in less apopto- switch in response to hypoxia. Interfer-
defense against atherosclerosis. In a sis (Dong et al. 2009, Yin et al. 2007). On ence with angiogenesis in the plaque can
recent paper, it was shown that sheer the other hand, differential miRNA ex- thus be envisioned at different levels. The
stress is capable of inducing endothelial pression in infracted, and border zone question whether systemic administra-
miR-21. This miRNA causes up-regula- areas were observed (Dong et al. 2009). tion of specific inhibitors or antagonists
tion of endothelial nitric oxide synthase These findings imply an important role can be sufficiently targeted to (unstable)
and reduces endothelial cell apoptosis for miRNA in myocardial infarction. plaques or whether local delivery should
(Weber et al. 2010). The potential ather- Therapeutic interference may add to a be explored with the use of specific
oprotective effects of this miRNA merit further preservation of previously ische- devices remains.
further investigation in atherosclerotic mic myocardium especially in the setting
models. In addition, miRNAs are in- of primary coronary interventions. Fur-  Diagnostic, Therapeutic, and
volved in the prevention of leukocyte thermore, the possibility of systemic
Future Perspectives
adhesion. Vascular cell adhesion mole- detection may bring in new early diag-
cule-1 (VCAM-1)-mediated adhesion nostic tools. As described previously, miRNAs play
can be inhibited by miR-126 in human Angiogenesis is closely related to important roles in processes that also
umbilical vein endothelial cells. De- plaque destabilization and rupture contribute to plaque vulnerability. Anti-
creased expression of miR-126 up-reg- (Figure 2). miRNAs have been reported F2 angiogenic properties of the miR-17-92
ulates vascular cell adhesion molecule- to influence angiogenesis (Bonauer et al. cluster have recently been found (Doebele
1-1 expression, which in turn enhances 2009). These miRNAs are called angio- et al. 2010). miRNA-based inhibition of
leukocyte adherence to the endothelium miRs. With the use of a hind limb intraplaque angiogenesis may be a prom-
(Harris et al. 2008). Also, the expression ischemia model, it has been shown that ising approach to prevent intraplaque
of E-selectin on vascular endothelial miR-92a controls angiogenesis in mice. hemorrhage and subsequent rupture. In
cells can be manipulated by miRNAs Ischemic injury caused miR-92a up- addition, reducing inflammation by
(miR-E1 and miR-E2). In human aorta regulation and blockade of miR-92a interfering with cellular interactions or
endothelial cells, suppression of E-selec- with systemic administration of antago- with proinflammatory cell products (such
tin expression and inhibition of leuko- mir-92a increased recovery of blood flow as metalloproteinases) may further stabi-
cyte adhesion has been found (Bonauer et al. 2009). Some reviews have lize plaques.
(Yoshizaki et al. 2008). On the other been published addressing this topic in The main difficulty with the use of
hand, endothelial cells can be stimulat- the recent past (Kuehbacher et al. 2008, miRNAs for therapeutic purposes is the
ed by tumor necrosis factor to generate Wang and Olson 2009, Wu et al. 2009). delivery of the drug to target cells. There
miRNAs related to proatherogenic prop- Pro- as well as antiangiogenetic miRNAs have been a number of attempts to
erties (Suarez et al. 2010). have been found (Table 1). Silencing of T1 overcome this problem, with the use of
In the development of atherosclerotic Dicer in endothelial cells led to the up- techniques such as conjugation and
plaques, the immune system plays a regulation of thrombospondin-1 that is a formulation. Conjugation includes direct
crucial role. Toll-like receptors (espe- known inhibitor of angiogenesis. It is attachment of peptides or antibodies
cially TLR4) have extensively been im- postulated that miRNAs Let-7 and the to the noncoding RNAs that facilitate
plicated in atherosclerotic plaque miR-17-92 cluster are targeted at throm- cellular uptake. Formulation includes
development as well as destabilization bospondin-1 and inhibitors of these two complex lipid emulsions, synthetic lipo-
(Pasterkamp et al. 2004). Interestingly, miRNAs reduced endothelial cell sprout- somes, and nanoparticles, among other
translational regulation of TLR4 by ing and matrigel tube formation in vitro carrier complexes (Rooij van et al. 2008,
miRNA has been described in a cholan- (Kuehbacher et al. 2008, Wang and Olson Silvestri et al. 2009), For example, the
gitis model (Chen et al. 2007). Whether 2009). Down regulation of Drosha by conjugation of miRNAs to cholesterol
such regulatory control is possible in siRNA resulted in vitro in a significant enhances cellular uptake of these sub-
other cell types remains to be deter- reduction of capillary sprouting and tube stances. Cholesterol-bound nucleotides
mined. Furthermore, miR-147 is part of formation but no reduced angiogenesis (“antagomirs”) have been proven effec-
a negative feedback loop in lipo-poly- in vivo(Kuehbacher et al. 2007). Finally, tive and specific silencers of endogenous
saccharide-stimulated monocytes (Liu miRNAs influence angiogenesis at the miRNAs in mice (Krutzfeldt et al. 2005).

TCM Vol. 20, No. 2, 2010 67


Figure 2. miRNAs in atherosclerotic plaque formation. The potential positive or negative regulation by miRNAs on a number of atherosclerotic
plaque characteristics is shown. The main factors are neointimal formation, inflammation, apoptosis, and angiogenesis, including hypoxia. See
text for further explanation. SMC, smooth muscle cell; VCAM, vascular cell adhesion molecule-1.

These modified RNA molecules have In the cardiovascular field, miRNA-145 published (Tatsuguchi et al. 2007). The
sequences complementary to target miR- has been studied intensively for its results presented previously are promis-
NAs. Intravenous injection of an antago- expected therapeutic power in atheroscle- ing, but still a lot of experiments are
nist of the hepatocyte-specific miR-122 rotic disease. It is the most abundant necessary before clinical therapy can be
(antagomir-122) led to decreased plasma miRNA in arteries (Ji et al. 2007) and in initiated; for example, the cellular and
cholesterol levels and significantly im- differentiated vascular smooth muscle molecular mechanisms and potential side
proved liver steatosis in an obese mouse cells (Cheng et al. 2009). Adenovirus- effects of miRNA-based therapy need to be
model (Esau et al. 2006). The first human mediated gene transfer of miRNA-145 in determined (Zhang 2009). Among the
phase I studies are currently being per- rat balloon-injured carotid arteries inhib- difficulties of therapeutic interventions
formed with the use of locked nucleic ited neointimal lesion formation (Cheng et are the invasive administration by injec-
acid–modified oligonucleotide (SPC3649) al. 2009). Knockout of miRNA-145 tion and the potential off-target effects due
complementary to miR-122, which suc- resulted in formation of neointima in to the broad spectrum of cellular pathways
cessfully suppressed hepatitis C virus mouse arteries (Boettger et al. 2009). In regulated by single miRNAs (Yang and
concentration in the bloodstream in addition, inhibition of miR-21 expression Mattes 2008).
primates (Lanford et al. 2010). Other via antisense oligonucleotide-mediated The discovery of myocardial-specific
promising miRNA-based therapeutics miRNA depletion significantly decreased miRNAs and the fact that they can be
are under investigation for treatment of neointima formation after angioplasty in detected in peripheral blood samples
oncologic pathologic conditions such as rats (Ji et al. 2007). Suppression of miR-21 have paved the way for diagnostic appli-
prostate cancer (Bonci et al. 2008), via antisense-mediated depletion has also cation. On the one hand, a large group of
leukemia (McLaughlin et al. 2007), and been reported to act antihypertrophic in patients where this may be of great
breast cancer(Liang et al. 2007, Valastyan animal models (Cheng et al. 2007), al- benefit are those presenting with acute
et al. 2009). though contrary results have also been chest pain. The triage of these patients is

68 TCM Vol. 20, No. 2, 2010


Table 1. Atherosclerotic plaque characteristics affected by miRNAs
Characteristic Facilitating Inhibiting Effect Model

Angiogenesis miR-126, -17-92 miR-221/miR-222 Decreases plaque Hind limb ischemia


cluster, Let7b,f (Scalbert and Bril 2008), stability model, Dicer
(Scalbert and Bril 2008); miR-15b/miR-16, knockout, HUVECs,
miR-130a, -210, -378, miR-20a/b, -328 and the like
Hypoxia -296 (Wu et al. 2009); (Kuehbacher et al. 2008, Initiates HUVECs
and miR-27b Wu et al. 2009) angiogenesis
(Kuehbacher et al. 2008)
miR-210 (Panutsopulos
et al. 2005)
miR-210
(Fasanaro et al. 2008)
Apoptosis miR-214 miR-1 (Tang et al. 2009) Apoptosis of Ischemia reperfusion
(Cheng et al. 2005) miR-1d, 7, 148, 204, 210, VSMCs rat model
miR-15, 16 216, and 296 Decreases plaque (Tang et al. 2009)
(Guo et al. 2009) (Cheng et al. 2005) stability Antisense inhibitor
Reduces Bcl-2, in HeLa cells
increases (Cheng et al. 2005)
caspases 3, 8, 9 Culture-activated
HSCs
Inflammation miR-155 Down regulation Human monocyte-
(Ceppi et al. 2009) of VCAM-1 derived dendritic cells
miR-126 (Ceppi et al. 2009)
(Harris et al. 2008) HUVECs
(Harris et al. 2008)
MMPs/TLRs miR21 miR188 Decreases plaque
(Gabriely et al. 2008) (Mishra et al. 2009) stability
Cell adhesion miR-126 Inhibits VCAM-1 Knockdown
(Harris et al. 2008) expression on transfections
endothelial cells in HUVECs
Neointimal lesion miR-21 Initiation of VSMC Balloon injury and
formation (Ji et al. 2007) proliferation, dedifferentiated
decreased VSMCs in vitro
apoptosis (Ji et al. 2007)
The effects of different miRNAs on plaque (in)stability are summarized. Facilitating and inhibiting miRNAs and their specific modes of action are
mentioned. HUVEC, human umbilical vein endothelial cell; HSC, hepatic stellate cell; MMP, matrix metalloproteinases; TLR, Toll-like receptor;
VSMC, vascular smooth muscle cell; VCAM-1, vascular cell adhesion molecule 1.

now based on history, electrocardio- edge about miRNA regulation in the processes related to the risk of athero-
gram, and biomarkers (especially tropo- context of plaque biology and whether sclerotic plaque rupture. More plaque-
nin). Levels of miR-208, a cardiac- certain miRNAs are plaque specific specific miRNA research is needed. Fu-
specific nucleotide, correlate with the could give research in this field a boost. ture developments with the use of
classic biomarker cardiac troponin I (Ji Finally, measurable circulating miR- miRNA-based strategies may give us the
et al. 2009). Furthermore, miR-1 con- NAs within the body raise the hypothesis possibility for ultrarapid diagnosis in
centration in plasma of myocardial that the miRNA signature could discrim- suspected acute coronary syndrome and
infarction patients was lower than inate between patients with stable and heart failure patients, to discriminate
healthy controls (Ai et al. 2010). Another unstable atherosclerotic plaques. Dis- between high- and low-risk patients and
approach aiming at early diagnostics crimination between these forms of to stabilize unstable plaques.
may be to look for miRNAs related to plaques may lead to a patient-tailored
plaque rupture instead of myocardial approach and help to choose between References
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