Micro RNA: New aspect in pathobiology of preeclampsia?
Harapan Harapana,*, Mohd. Andalasa, Diky Mudhakirb, Natalia C. Pedrozac,
Saurabh V Laddhad, Jay R. Anande
aObstetrics and Gynecology Department, School of Medicine Syiah Kuala University, Banda Aceh, Indonesia
bSchools of Pharmacy, Bandung Institute of Technology (ITB), Bandung, Indonesia
cViral Vector Core and Gene Therapy, Neuroscience Group, University Research Center, University of Antioquia,
dG N Ramachandran Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology (CSIR),
Mall Road, Delhi 110007, India
eDepartment of Pharmacology, National Institute of Pharmaceutical Education and Research, Guwahati, India
Received 29 June 2011; accepted 28 September 2011
Available online 14 February 2012
esis theory; diagnosis and treatment approach to some diseases. Some scientifically proven theories
have been proposed to seek the association of alterations of miRNA expression to incidences and
severity of preeclampsia (PE). In this review we explore the result of such investigations that discuss
the association of miRNA and PE along with the role of various mRNAs in PE pathogenesis.
? 2012 Ain Shams University. Production and hosting by Elsevier B.V. All rights reserved.
The discovery of miRNA in 1993, by Ambros et al. has had a huge influence in pathogen-
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
*Corresponding author. Address: Obstetrics and Gynecology Depart-
ment, School of Medicine Syiah Kuala University, Jl. Tanoeh Abe,
Darussalam, Banda Aceh 23111, Indonesia. Tel.: +6285260850805.
E-mail address: email@example.com (H. Harapan).
1110-8630 ? 2012 Ain Shams University. Production and hosting by
Elsevier B.V. All rights reserved.
Peer review under responsibility of Ain Shams University.
Production and hosting by Elsevier
The Egyptian Journal of Medical Human Genetics (2012) 13, 127–131
Ain Shams University
The Egyptian Journal of Medical Human Genetics
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biogenesis and mechanism action of miRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Molecular mechanisms of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
The role of miRNA in preeclampsia pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Preeclampsia (PE) is a disease of pregnancy characterized by
hypertension (defined as systolic blood pressure P140 mm
Hg or diastolic blood pressure P90 mm Hg) and proteinuria
(300 mg or greater in a 24-h urine specimen and/or protein to
creatinine ratio of >0.30), developing after 20 weeks of gesta-
tion [1–3]. It has been estimated that PE affects 3–5% of preg-
nancies worldwide , recently, it has been reported that PE
complicates 3–8% of pregnancies . There is much evidence
shown that PE originates in the placenta [6,7] and thus the pla-
centa is believed as the central basis to the pathogenesis of PE
. But the molecular basis for placental dysregulation of these
pathogenic factors remains unknown. Many hypotheses have
emerged that attempt together a causal framework for the dis-
ease, causing PE to be named the ‘disease of theories’ .
MicroRNAs (miRNAs) are small, noncoding RNAs ?22
nucleotides (nt) in length that regulate gene expression, with
important functions in the regulation of a variety of biologic
processes involved in development, cell differentiation, regula-
tion of cell cycle, metabolism and apoptosis [10–12]. Albeit only
1% of the genomic transcripts in mammalian cells encode miR-
NA , miRNAs are predicted to control the activity of more
than 60% of all protein-coding genes . It has been estimated
that miRNAs regulate ?30% of human genes [10,15].
MicroRNAs regulate mRNA, which encodes proteins that
modulatecellular functions,therefore, miRNAs play important
roles in physiological homeostasis in health and pathophysio-
logical derangement in disease . MicroRNAs are known to
have function in pathological process and prognosis of diseases
such as diabetes , neurodegenerative disorder , gastroin-
nucleotide polymorphism (SNP) in the processing machinery
and target binding sites genes of miRNA affects cancer risk,
treatment efficacy and patient prognosis . Certain miRNAs
are tissue-specific and the temporal expression of the tissue-spe-
pathological status of the corresponding organs .
Research conducted by Pineles et al.  shows that PE is
associated with alterations in placental miRNA expression.
This research reported that miR-210 and -182 are expressed dif-
with control subjects . In this review we will discuss the role
of miRNA as a new aspect in pathophysiology of PE.
2.1. Biogenesis and mechanism action of miRNA
The first report on miRNA was presented in 1993 by Ambros
et al. who described a 22-nucleotide RNA in Caenorhabditis
elegans encoded by the lin-4 gene, which can bind to the lin-
14 transcript and interfere with its expression . Functional
studies indicate that miRNAs participate in the regulation of
almost every cellular process investigated so far and that
changes in their expression are associated with many human
MicroRNAs are processedfrom RNA polymeraseII (RNA-
PII)-specific transcripts of independent genes or from introns of
protein-coding genes . These initial miRNA precursors,
known as pri-miRNAs, are processed into ?70 nt hairpin struc-
tures known as pre-miRNAs – in the nucleus – by a nuclear en-
zyme complex known as the microprocessor that contains an
ing protein – DiGeorge syndrome critical region 8 (DGCR8).
This process called as Drosha–DGCR8 step [22,24]. Drosha is
cleave the 50and 30ends, releasing the pre-miRNA . Some
pre-miRNAs are produced from very short introns (mirtrons)
that bypass the Drosha–DGCR8 step .
The pre-miRNA is exported from the nucleus to the
cytoplasm by Exportin-5 (XPO5) . In the cytoplasm, the
pre-miRNA is further cleaved by another RNase III enzyme –
Dicer, which removes the loop to yield the ?22 nucleotide miR-
NA duplex . After being unwound by a helicase, one strand
of miRNA is destined to be the mature miRNA called as guide
strand and the complementary strand – called as passenger
strand or miRNA*– is rapidly degraded . The thermody-
namic stability of the miRNA duplex termini and the identity
of the nucleotides in the 30overhang determine which strands
act as the guide strand . Then the guide strand is incorpo-
rated into a miRNA-induced silencing complex (miRISC)
Guided by the sequence complementarity between the small
RNA and the target mRNA, miRNA–RISC-mediated gene
inhibition is commonly divided into three processes: (a) site-
specific cleavage, (b) enhanced mRNA degradation and (c)
translational inhibition .
The miRISC–mRNA interaction can lead to several modes
of direct and indirect on translational repression . Direct
on translational repression involved: (a). Initiation block: The
miRISC inhibits translation initiation by interfering with
ment or by antagonizing 60S subunit joining and preventing
mature ribosomal drop-off, the 40S/60S ribosomes are dissoci-
ated from mRNA, stalled or slowed elongation, the 40S/60S
ribosomes are prohibited from joining during the elongation
process or facilitating proteolysis of nascent polypeptides
[13,25,28]. The indirect on translational repression occurs via
mRNA deadenylation and degradation [13,28]. Deadenylation
of mRNAs is mediated by glycine–tryptophan protein of
182 kDa (GW182) proteins – the components of miRISC,
poly(A)-binding protein (PABP), and Argonaute (AGO) pro-
128H. Harapan et al.
of the miRISC which are directly associated with miRNAs .
Then this molecule will interacts with the CCR4/CAF1 deaden-
ylase complex to facilitate deadenylation of the poly(A) tail
[22,25]. Following deadenylation, the 50-terminal cap is re-
moved by the decapping enzyme – decapping DCP1-DCP2
complex . Endonucleolytic cleavage and mRNA degrada-
tion that miRNA-mediated by AGO2 [22,29].
2.2. Molecular mechanisms of preeclampsia
Angiogenic factors such as placental growth factor (PlGF) and
vascular endothelial growth factor (VEGF) and their receptors
Flt1 [also known as vascular endothelial growth factor receptor
1 (VEGFR-1)], VEGFR-2, Tie-1, and Tie-2, are essential for
normal placental vascular development . Alterations in the
regulation and signaling of angiogenic pathways in early gesta-
tion contribute to the inadequate cytotrophoblast invasion seen
in PE . Additionally, perturbation of the renin–aldosterone–
angiotensin II axis, excessive oxidative stress, inflammation,
immune maladaptation, and genetic susceptibility may all con-
tribute to the pathogenesis of PE .
Several placentally derived ‘‘toxins’’ were suggested, includ-
ing cytokines, anti-angiogenic factors, syncytiotrophoblast
microparticles (STBM), and formed blood products activated
in the intervillus space .
The role of these anti-angiogenic factors such as soluble
fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng)
in early placental vascular development and in trophoblast
invasion is just the beginning to be explored in placental dys-
regulation. Hypoxia is likely to be an important regulator
. Oxidative stress was an attractive component as part of
the linkage . Reactive oxygen species could be generated
by the reduced perfusion of the placenta with the consequent
activation of monocytes and neutrophils passing through the
intervillus space. Oxidative stress would also stimulate the re-
lease of cytokines, antiangiogenic factors, microparticles and
other potential linkers .
Some factors such as genetic factors, oxidative stress, cate-
chol-O-methyltransferase (COMT) deficiency, hemoxygenase
deficiency and immunologic/inflammatory factors cause pla-
cental dysfunction which leads to angiogenic imbalance, in-
crease sFlt1 and sEng, decrease PlGF and VEGF [8,32,33].
sFlt1 and sEng levels have been shown to be elevated in the
serum of preeclamptic women, as compared to those of normal
pregnant women, weeks before the appearance of overt clinical
manifestations of the disease [34,35]. Compared to normo-ten-
sive controls, in patients with severe PE, free PlGF and VEGF
levels are significantly declined [34,35] and sFlt1 levels are sig-
nificantly elevated .
It is clear that the increase of sFlt1 expression associated
with decreased PlGF and VEGF signaling causes inadequate
placental vascular development [34,37,38]. These alterations
cause widespread endothelial dysfunction that results in hyper-
tension, proteinuria, and other systemic manifestations of pre-
2.3. The role of miRNA in preeclampsia pathogenesis
The first research that linked miRNA and PE was conducted
by Pineles et al.  The study was performed to determine
whether PE and small-for-gestational age (SGA) are associ-
ated with alterations in placental miRNA expression. Thus
they evaluated placental miRNAs’ expression from patients
with PE, SGA, PE + SGA along with a control group. They
found that seven miRNAs (miR-210, miR-155, miR-181b,
miR-182*, miR-200b, miR-154*, and miR-183) were signifi-
cantly higher expressed between PE + SGA and the control
group. The expression of miR-182 and miR-210 was signifi-
cantly higher in PE than in the control group. Based on Gene
Ontology (GO) analysis, miR-182 has a role to down-regulate
anti-apoptosis genes. They speculated that high expression of
miR-182 in PE may contribute to the increased apoptosis in
the placentas of patients with PE. The targets of both miR-
182 and miR-210 are enriched in immune processes, which
support the association between abnormal immune responses
and PE as descripted previously by Kim et al. . Beside that,
angiogenin and VEGF-b are potential targets of miR-182 and
miR-182*, respectively . These molecules have a role in
angiogenesis. A study by Yang et al.  elucidates miRNA
essentiality, that in mice with deficient miRNA, defective angi-
ogenesis is caused that leads to embryonic lethality.
A study with small sample in China found the expression of
miR-130a, miR-181a, miR-222, miR-16, miR-26b, miR-29b
and miR-195 in the placenta of severe PE women . The
other research reported that miR-16, miR-29b, miR-195,
miR-26b, miR-181a, miR-335 and miR-222 were significantly
increased in placenta from women with severe PE . This re-
search revealed that some angiogenic growth factors were po-
tential targets of the altered miRNA, such as cysteine-rich 61
(CYR61), PlGF, VEGF-A which were targets of miR-222,
miR-335 and miR-195, respectively . It describes the role
of this angiogenics factors for the development of PE. It is well
known that the expressions of VEGF-A and VEGF receptor-1
are down-regulated in the cytotrophoblasts of PE placenta
[32,43]. Several articles reviewed by Lam et al.  provide suf-
ficient evidence that PlGF is also dysregulated in serum or the
placental tissue of women with PE.
The research by Mo et al.  found that CYR61 is essen-
tial for placental development and vascular integrity. Gellhaus
et al.  found that CYR61 is significantly decreased in PE
placenta. CYR61 is a secreted matrix protein expressed by
nearly all types of vascular cells and trophoblasts and impli-
cated in diverse cellular processes such as proliferation, migra-
tion, differentiation, and adhesion. It was found that the
expression of CYR61 in human placenta was significantly low-
er than that of the normal control . Recently, a study re-
ported that overexpression of miR-155 contributes to PE
development by targeting and down-regulating angiogenic reg-
ulating factor CYR61 . It was also reported that CYR61
has been demonstrated to be one of the important early angio-
genic factors during pregnancy, this role is probably because
CYR61 can induce the expression of VEGF .
Poliseno et al.  found that overexpression of miR-221/
222 inhibits tube formation, migration, and wound healing
in response to stem cell factor in human umbilical endothelial
cells (HUVEC). This effect, arises because c-kit is a target of
miR-221/222. c-kit is a tyrosine kinase receptor for stem cell
factor and has been shown to promote survival, migration,
and capillary tube formation HUVEC .
The other study by Zhu et al.  was conducted in China
population. They investigated that 34 miRNAs were expressed
differentially in PE placentas, compared to normal placentas.
Of these, 11 microRNAs were over-expressed, and 23 miRNAs
were under-expressed in PE placentas. miR-518b showed sig-
nificant overexpression in severe PE vs control; miR-18a, -
363, and -542-3p were significantly underexpressed in severe
PE vs control. miR-152 showed significant overexpression in
mild PE vs control specimens and in severe PE vs control spec-
imens. miR-411 and miR-377 were under-expressed in mild PE
vs control specimens and in severe PE vs control. Zhu et al.
 also found that miR-210 was significantly underexpressed
in mild PE vs the other two groups; while significant overex-
pression was found in severe PE vs all other groups. In their
comments, they mention that the increase in miR-210 expres-
sion in sPE induced by the focal regions of ischemia/hypoxia
in placentas is the cause of poor placentation in PE pregnan-
cies, as a previous study showed that the expression of miR-
210 was increased on exposure to hypoxia . They specu-
lated the decrease of miR-210 in mPE to be a compensatory
mechanism in the pregnancies with mPE, but there is no suffi-
Recently, Enquobahrie et al.  found that eight miR-
NAs were differentially expressed (miR-210 up-regulated
and 7 – miR-328, miR-584, miR-139-5p, miR-500, miR-
1247, miR-34C-5p and miR-1-down-regulated) among PE
cases compared with controls. These miRNAs target genes
that participate in organ/system development (cardiovascular
and reproductive systems), immunologic dysfunction, cell
adhesion, cell cycle, and signaling. In their comment consis-
tent with the other scientist, they stated that miR-210 plays
roles in endothelial cell response to hypoxia, formation of
capillary-like structures, vascular endothelial growth factor –
driven cell migration, cell differentiation, and survival, events
that are integral to PE pathogenesis. Enquobahrie et al. 
utilizing the results of previous study conducted by Ikeda
et al.  speculated that miR-1 influences risk of PE through
its effect on calcium signaling. They demonstrated that miR-1
influences calcium signaling through negative regulations of
the calmodulin-coding mRNAs, Mef2a and Gata4, mainly
in smooth muscle cells. It is believed that PE has associated
with abnormal calcium metabolism and related consequences
The association between PE and altered miRNA expression
suggests the possibility of a functional role for miRNA in this
disease. These different miRNAs may play an important role
in the pathogenesis of PE and may become diagnostic markers
and therapeutic target for PE.
In summary, we have shown that there are many scientific evi-
dences that have proven the fact that the differential placental
and plasma miRNA expression is associated with PE. Some re-
searches also identify novel candidate miRNAs (and pathways
they regulate) that may be of etiologic relevance in the patho-
genesis of PE. It provides novel targets for further investiga-
tion of the pathogenesis of PE and these differential
miRNAs may be potential markers for the diagnosis and pro-
vide a potential therapeutic target for PE. Further investiga-
tions on posttranscriptional regulation in PE to evaluate
biologic effects of identified miRNAs (including the confirma-
tions of miRNA and target gene interactions) are needed.
4. Disclosure statement
There is no conflict of interest in writing of this manuscript.
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