A Major Role In Cardiomyopathy Biology Essay

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the heart muscle characterized by cardiac dysfunction. Several miRNAs including
those involved in heart development are found to be dysregulated in cardiomyopathy.
These miRNAs act either directly or indirectly by controlling the genes involved in
normal development and functioning of the heart. Indirectly it also targets modifier
genes and genes involved in signaling pathways. In this review, the miRNAs involved
in heart development, including dysregulation of miRNA which regulate various genes,
modifiers and notch signaling pathway genes leading to cardiomyopathy are
discussed. A study of these miRNAs would give an insight into the mechanisms
involved in the processes of heart development and disease. Apart from this, the
information gathered from these studies would also generate suitable therapeutic
targets in the form of antagomirs which are chemically engineered oligonucleotides
used for silencing miRNAs.
MICRO RNA REGULATION DURING CARDIAC DEVELOPMENT AND
REMODELING IN CARDIOMYOPATHY
Abstract
miRNAs have been found to play a major role in cardiomyopathy, which is a disease of the heart
muscle characterized by cardiac dysfunction. Several miRNAs including those involved in heart
development are found to be dysregulated in cardiomyopathy. These miRNAs act either directly
or indirectly by controlling the genes involved in normal development and functioning of the
heart. Indirectly it also targets modifier genes and genes involved in signaling pathways. In this
review, the miRNAs involved in heart development, including dysregulation of miRNA which
regulate various genes, modifiers and notch signaling pathway genes leading to cardiomyopathy
are discussed. A study of these miRNAs would give an insight into the mechanisms involved in
the processes of heart development and disease. Apart from this, the information gathered from
these studies would also generate suitable therapeutic targets in the form of antagomirs which are
chemically engineered oligonucleotides used for silencing miRNAs.
Introduction
Cardiomyopathy is a disease of the heart muscle characterized by cardiac dysfunction,
arrhythmia, heart failure and sudden death. It is a major cause of morbidity and mortality
worldwide. Cardiomyopathies can be classified into 2 major groups based on predominant organ
involvement: Primary cardiomyopathies (genetic, nongenetic, acquired) are those confined to
heart muscle and Secondary cardiomyopathies which show pathological myocardial involvement
as part of a large number and variety of generalized systemic (multiorgan) disorders (Elliott P et
al., 2008 ; Barry J. M et al, 2006).
ManuscriptmiRNAs have been found to play a major role in cardiomyopathy, which is a disease of the heart
muscle characterized by cardiac dysfunction. Several miRNAs including those involved in heart
development are found to be dysregulated in cardiomyopathy. These miRNAs act either directly
or indirectly by controlling the genes involved in normal development and functioning of the
heart. Indirectly it also targets modifier genes and genes involved in signaling pathways. In this
review, the miRNAs involved in heart development, including dysregulation of miRNA which
regulate various genes, modifiers and notch signaling pathway genes leading to cardiomyopathy
are discussed. A study of these miRNAs would give an insight into the mechanisms involved in
the processes of heart development and disease. Apart from this, the information gathered from
these studies would also generate suitable therapeutic targets in the form of antagomirs which are
chemically engineered oligonucleotides used for silencing miRNAs.
Introduction
Cardiomyopathy is a disease of the heart muscle characterized by cardiac dysfunction,
arrhythmia, heart failure and sudden death. It is a major cause of morbidity and mortality
worldwide. Cardiomyopathies can be classified into 2 major groups based on predominant organ
involvement: Primary cardiomyopathies (genetic, nongenetic, acquired) are those confined to
heart muscle and Secondary cardiomyopathies which show pathological myocardial involvement
as part of a large number and variety of generalized systemic (multiorgan) disorders (Elliott P et
al., 2008 ; Barry J. M et al, 2006).
It is also considered as a disease of sarcomere and cytoskeleton and recent studies have revealed
new facets about the role of micro RNAs in cardiac development and remodeling. A growing
body of exciting evidence suggests that miRNAs are regulators of cardiovascular cell
differentiation, growth, proliferation, angiogenesis and apoptosis. It has provided glimpses of
undiscovered regulatory mechanisms and potential therapeutic targets for the treatment of
cardiomyopathies.
miRNA, an endogenous ~22nt RNA, plays important regulatory roles in animals and plants.
They cleave the target mRNA or translationally repress them. The first miRNA discovered, was
lin-4 in C. elegans, which was found to produce a pair of short RNA transcripts that regulate the
timing of larval development by translational repression of lin-14, which encodes a nuclear
protein (Lee R.C et al. 1993). Since the discovery of let-7, thousands of miRNAs have been
identified in organisms as diverse as viruses, worms, and primates through random cloning and
sequencing or computational prediction. A hepta nucleotide sequence at the 5’ end of the
miRNA is essential in the base pairing specificity with the 3’end of the mRNA (Gregory P. A., et
al. 2008).
Role of miRNA in heart development and function:
Role of miRNAs in heart development was identified in Zebrafish and mice by targeting the
Dicer protein which is the main component of miRNA machinery. Zebrafish lacking maternal
and endogenous Dicer exhibited heart developmental defects (Giraldez A. J et al. 2005 ;
Wienholds E. et al. 2003). Cardiac-specific deletion of Dicer in mice resulted in pericardial
edema and poorly developed ventricular myocardium resulting in embryonic lethality (Zhao Y.
et al 2007). Adult mice lacking Dicer in the myocardium revealed high incidence of sudden
death, cardiac hypertrophy, reactivation of the fetal cardiac gene program (da Costa Martins P. A
et al 2008). Further studies also showed that additional miRNAs, miR1, miR133, miR1/133
(bicistronic), miR21 and miR138 are involved in the regulation of heart development.
miR-1/miR-133: The most abundant miRNA in cardiac myocytes and also the first miRNA
implicated in heart development was miR-1(Zhao Y. et al 2007). miR-1 and -133 are expressed
in cardiac and skeletal muscles and are transcriptionally regulated by the myogenic
differentiation factors MyoD, Mef2, and serum response factor (SRF) (Chen J. F et al 2008,
Kwon C et al. 2005 ; Lagos-Quintana M et al 2001 ; Rao P. K et al 2006 ; Sokol N. S et al
2005 ; Zhao Y et al 2005).
Targeted deletion of the muscle-specific miRNA, miR-1-2, was found to cause ventricular septal
defects (VSD) in mice embryos resulting in immediate death and in some embryos it caused
pericardial edema which contributes to embryonic mortality (Yu X et al 2008). In mice that
survived postnatally, some died within months due to rapid dilatation of the heart and ventricular
dysfunction, while many others suffered sudden cardiac death because of abnormalities in
cardiac conduction and repolarization. miR-1-2 also directly targets irx5, which is known to
repress the potassium channel, Kcnd2, ensuring coordinated cardiac repolarization (Costantini D.
L et al 2005). In adult miR-1-2 mutants, cardiomyocyte division continues postnatally due to
abnormalities in cell-cycle leading to hyperplasia of the heart.
miR-1 levels are low during cardiac development but seem to increase as development
progresses (Zhao Y et al 2005). In mice, overexpression of miR-1 under the control of the
myosin heavy chain (MHC) promoter negatively regulates cardiac growth, partly by inhibiting
implicated in heart development was miR-1(Zhao Y. et al 2007). miR-1 and -133 are expressed
in cardiac and skeletal muscles and are transcriptionally regulated by the myogenic
differentiation factors MyoD, Mef2, and serum response factor (SRF) (Chen J. F et al 2008,
Kwon C et al. 2005 ; Lagos-Quintana M et al 2001 ; Rao P. K et al 2006 ; Sokol N. S et al
2005 ; Zhao Y et al 2005).
Targeted deletion of the muscle-specific miRNA, miR-1-2, was found to cause ventricular septal
defects (VSD) in mice embryos resulting in immediate death and in some embryos it caused
pericardial edema which contributes to embryonic mortality (Yu X et al 2008). In mice that
survived postnatally, some died within months due to rapid dilatation of the heart and ventricular
dysfunction, while many others suffered sudden cardiac death because of abnormalities in
cardiac conduction and repolarization. miR-1-2 also directly targets irx5, which is known to
repress the potassium channel, Kcnd2, ensuring coordinated cardiac repolarization (Costantini D.
L et al 2005). In adult miR-1-2 mutants, cardiomyocyte division continues postnatally due to
abnormalities in cell-cycle leading to hyperplasia of the heart.
miR-1 levels are low during cardiac development but seem to increase as development
progresses (Zhao Y et al 2005). In mice, overexpression of miR-1 under the control of the
myosin heavy chain (MHC) promoter negatively regulates cardiac growth, partly by inhibiting
translation of heart and neural crest derivative-2 protein, Hand2, which is involved in ventricular
myocyte expansion (Zhao Y et al 2005). In Drosophila, dmiR-1(miR-1 of drosophila) plays an
important role in differentiation of cardiac progenitor cells by targeting transcripts of delta, a
ligand involved in Notch signaling pathway, which regulates the expansion of cardiac and
muscle progenitor cells (Kwon C et al 2005).
vaguely defined. This particular miRNA is stress induced and is a regulator of cardiac growth
(Van Rooij E et al 2006). Hence its interaction with the HSP-70 gene family needs to be
elucidated, as HSP is also a cardiac specific development gene. Sabatel et al(2011) showed that
over-expression of miR-21 reduced endothelial cell proliferation, migration, and tube formation
by targeting RhoB, whereas knockdown of miR-21 led to an opposite effect (Sabatel C et al
2011)
miR-138:
embryo, but within the zebrafish heart, it is specifically expressed in the ventricular chamber
(Morton S. U et al 2008). Disruption of miR-138 function led to the expansion of the
atrioventricular canal into the ventricle and failure of maturation of ventricular cardiomyocytes.
It has thus been suggested that other region-specific miRNAs may reinforce known signaling and
transcriptional networks that establish patterns of gene expression throughout the
developing heart tube (Heitzler P. & Simpson P. 1991). Hence the relation between modifier
genes and miRs during embryogenesis needs to be substantiated.
miRNA in cardiomyopathy and cardiac remodeling:
miRNA mediated gene repression is an important regulatory mechanism to modulate
fundamental cellular processes such as the cell cycle, growth, proliferation, phenotype, death,
which in turn have major influences on pathophysiological outcomes like cardiac fibrosis,
hypertrophy, angiogenesis, and heart failure(Catalucci D et al 2009 ; Thum T et al 2007 ; Thum
T et al 2008). Although miRNAs are highly expressed in heart, their role in heart diseases
especially cardiomyopathies still remains unclear.
Multiple aberrant miRNA expression is a remarkable characteristic of the hypertrophic heart (Y
Cheng et al 2007). The dysregulation and the time course changes of these multiple aberrantly
expressed miRNAs match the complex process of cardiac hypertrophy formation in which
several genes have been reported to be dysregulated (Dorn II G. W., Hahn H. S. 2004).
Determining the effects of these dysregulated miRNAs in cardiac hypertrophy is the prerequisite
for a novel research on cardiomyopathy.
It was reported that a cardiac-specific knockout of the Dicer gene leads to rapidly progressive
dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Dicer expression decreased
in end-stage human DCM and heart failure. These findings suggest that Dicer function and
miRNAs play critical roles in normal cardiac function and heart diseases especially during heart
failure (Chen J. F et al 2008).
miR-1/miR-133: miR-133 and miR-1 play critical roles in cardiac hypertrophy. In human and
mouse models of cardiac hypertrophy, decreased expression of both miR-133 and miR-1 is
reported. In vitro, overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In
contrast, suppression of miR-133 induced hypertrophy. In vivo inhibition of miR-133 by a single
infusion of an antagomir caused marked and sustained cardiac hypertrophy. RhoA, a GDP-GTP
exchange protein (regulator of cardiac hypertrophy); Cdc42, a signal transduction kinase
(implicated in hypertrophy); and Nelf-A/WHSC2, a nuclear factor (involved in cardiogenesis)
are all targets of miR-133 (Carè A et al 2007).
When overexpressed in normal or infarcted rat hearts, miR-1 aggravates arrhythmogenesis and
elimination of miR-1 by an antisense inhibitor relieved arrhythmogenesis. The target of miR-1
was found to be gap junction protein a1 (GJA1) which encodes Cx43, the main cardiac gap
junction channel important for conductance in the ventricles (Luo X et al 2007) and potassium
inwardly-rectifying channel, subfamily J, member 2 (KCNJ2) (Yang B et al 2007).
miR-21: Inhibition of miR-21 in neonatal rat cardiomyocytes by transfecting locked nucleic acid
(LNA)-modified antisense oligonucleotides(miR-LNA) to miR-21 or miR-18b induced myocyte
hypertrophy while transfection of miR-21 and miR-18b duplexes slightly decreased
cardiomyocyte size and decreased hypertrophy thus suggesting their role in regulating
mouse models of cardiac hypertrophy, decreased expression of both miR-133 and miR-1 is
reported. In vitro, overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In
contrast, suppression of miR-133 induced hypertrophy. In vivo inhibition of miR-133 by a single
infusion of an antagomir caused marked and sustained cardiac hypertrophy. RhoA, a GDP-GTP
exchange protein (regulator of cardiac hypertrophy); Cdc42, a signal transduction kinase
(implicated in hypertrophy); and Nelf-A/WHSC2, a nuclear factor (involved in cardiogenesis)
are all targets of miR-133 (Carè A et al 2007).
When overexpressed in normal or infarcted rat hearts, miR-1 aggravates arrhythmogenesis and
elimination of miR-1 by an antisense inhibitor relieved arrhythmogenesis. The target of miR-1
was found to be gap junction protein a1 (GJA1) which encodes Cx43, the main cardiac gap
junction channel important for conductance in the ventricles (Luo X et al 2007) and potassium
inwardly-rectifying channel, subfamily J, member 2 (KCNJ2) (Yang B et al 2007).
miR-21: Inhibition of miR-21 in neonatal rat cardiomyocytes by transfecting locked nucleic acid
(LNA)-modified antisense oligonucleotides(miR-LNA) to miR-21 or miR-18b induced myocyte
hypertrophy while transfection of miR-21 and miR-18b duplexes slightly decreased
cardiomyocyte size and decreased hypertrophy thus suggesting their role in regulating
cardiomyocyte hypertrophy. The molecular basis of this regulation still needs to be established.
Hence the role of miR-21 in chromatin modelling of cardiomyocytes cannot be overlooked
(Tatsuguchi M et al 2007).
A study showed an increased expression of miR-21, miR-23, miR-24, miR-125b, miR-195, miR199a,
and miR-214, and decreased expression of miR-29c, miR-93, miR-150, and miR-181b in
mice subjected to chemicals which induced cardiac hypertrophy. Upon transfection into
cardiomyocytes, five of the miRNAs that were upregulated, viz. miR-23a, miR-23b, miR-24,
miR-195, and miR-214, were found to be capable of inducing hypertrophic growth. Whereas
transfection of miR-199a resulted in elongated spindle shapes myocytes reminiscent of the
elongated cardiac myocytes observed in dilated cardiomyopathy.
Cardiac specific overexpression of miR-195 was found to cause death in the first 2 weeks after
birth due to heart failure because of cardiac dilatation and in the rats that survived initially,
induction of cardiac growth with disorganization of cardiomyocytes occurred at 2 weeks of age,
which later progressed to a dilated cardiac hypertrophic phenotype by 6 weeks of age thus
suggesting the critical role played by miR-195 in cardiac remodeling (Van Rooij E et al 2006).
miR-29: The miR-29 family, which is downregulated after myocardial infarction, inhibits the
expression of several collagens and extracellular matrix proteins, thereby contributing to scar
formation and fibrosis, as seen in DCM, during heart failure.
miR-208: miR-208 is required for the development of cardiac hypertrophy and myocardial
fibrosis and it is also a positive regulator of MHC gene expression (van Rooij E et al 2007).
expression of several collagens and extracellular matrix proteins, thereby contributing to scar
formation and fibrosis, as seen in DCM, during heart failure.
miR-208: miR-208 is required for the development of cardiac hypertrophy and myocardial
fibrosis and it is also a positive regulator of MHC gene expression (van Rooij E et al 2007).
Regulation of Modifiers by miRNAs:
Stress is a major etiologic factor that may contribute to heart diseases. Stress overload can cause
tissue injury; cardiomyocyte death is considered an important cellular basis for stress-induced
injury in cardiomyopathies (Feuerstein G. Z., Young P. R. 2000). miR-199 family is rapidly
downregulated in cardiac myocytes under hypoxic conditions, relieving the repression of sirtuin
1 and hypoxia inducible factor 1-a in a model of hypoxia preconditioning. The miRNA that
repeatedly showed dynamic regulation after cellular stress is miR-21, which promotes cardiac
hypertrophy and fibrosis in response to pressure overload (Rane S et al 2009).
Under stress a change in expression of HSP70 in rat myocardium is observed. HSP70 protects
cardiomyocyte from stress induced injury by inhibiting Fas-mediated apoptosis (Basu N et al
2001). The levels of miR-1 was found to increase significantly in response to oxidative stress
which later reduced the levels of HSP70 favoring cardiomyocyte apoptosis, while decreased
levels of miR-1 favored cardiomyocyte survival (Xu C et al 2007).
The members of TGF-ß family have been found to have a cardioprotective role and are highly
induced in affected hearts. Their putative roles during atherogenesis, infarct healing, cardiac
repair and left ventricular remodeling have been proposed (Os I et al 2002). miR24a and
miR34a seem to have a strong and specific regulatory effect on TGF ß while miR-373 and miR34b
have a constitutive role (Schultz N et al 2011).
Stress is a major etiologic factor that may contribute to heart diseases. Stress overload can cause
tissue injury; cardiomyocyte death is considered an important cellular basis for stress-induced
injury in cardiomyopathies (Feuerstein G. Z., Young P. R. 2000). miR-199 family is rapidly
downregulated in cardiac myocytes under hypoxic conditions, relieving the repression of sirtuin
1 and hypoxia inducible factor 1-a in a model of hypoxia preconditioning. The miRNA that
repeatedly showed dynamic regulation after cellular stress is miR-21, which promotes cardiac
hypertrophy and fibrosis in response to pressure overload (Rane S et al 2009).
Under stress a change in expression of HSP70 in rat myocardium is observed. HSP70 protects
cardiomyocyte from stress induced injury by inhibiting Fas-mediated apoptosis (Basu N et al
2001). The levels of miR-1 was found to increase significantly in response to oxidative stress
which later reduced the levels of HSP70 favoring cardiomyocyte apoptosis, while decreased
levels of miR-1 favored cardiomyocyte survival (Xu C et al 2007).
The members of TGF-ß family have been found to have a cardioprotective role and are highly
induced in affected hearts. Their putative roles during atherogenesis, infarct healing, cardiac
repair and left ventricular remodeling have been proposed (Os I et al 2002). miR24a and
miR34a seem to have a strong and specific regulatory effect on TGF ß while miR-373 and miR34b
have a constitutive role (Schultz N et al 2011).
The renin-angiotensin system (RAS) is one of the most important modifiers in cardiomyopathy.
The angiotensin converting enzyme(ACE) is the key enzyme, involved in conversion of
angiotensin I to angiotensin II which is responsible for cardiac hypertrophy and heart failure
(Kawaguchi H. 2003) and miR145 has been found to regulate this enzyme(Small E et al 2010).
Hence it can be hypothesized that miRNAs have both positive and negative roles in
cardiomyopathies, especially in a heart failure phenotype; either as modifiers or by gene-gene
interaction and/or regulators of cardiogenesis. One such regulation could be in
signaling/transduction pathways.
Regulation of Signaling pathways by miRNAs and their role in cardiomyopathies
Understanding complex diseases like cardiomyopathies not only requires identification of genes
and upregulation/downregulation of miRNAs, but also of the proteins that are regulated and
signaling pathways that are affected by these miRNAs. Various intercellular signaling pathways
have been implicated in the control of cardiogenesis viz. Notch signaling, FGF signaling, BMP
signaling, Wnt/b-catenin signaling, Wnt/JNK pathways etc.
Notch signaling and cardiogenesis:
Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from
flies to humans, resulting in the generation of multiple cell types from equipotential precursors.
Notch signaling is also involved in angiogenesis and vasculogenesis. Notch signaling is a highly
conserved and a complex mechanism initiated by the interaction of Notch receptors with their
Understanding complex diseases like cardiomyopathies not only requires identification of genes
and upregulation/downregulation of miRNAs, but also of the proteins that are regulated and
signaling pathways that are affected by these miRNAs. Various intercellular signaling pathways
have been implicated in the control of cardiogenesis viz. Notch signaling, FGF signaling, BMP
signaling, Wnt/b-catenin signaling, Wnt/JNK pathways etc.
Notch signaling and cardiogenesis:
Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from
flies to humans, resulting in the generation of multiple cell types from equipotential precursors.
Notch signaling is also involved in angiogenesis and vasculogenesis. Notch signaling is a highly
conserved and a complex mechanism initiated by the interaction of Notch receptors with their
ligands both of which are transmembrane proteins whose extracellular domains are composed of
epidermal growth factor (EGF) like repeats (Eiraku M et al 2005). The Notch receptors include
the Notch1-4 in mammals and Notch in Drosophila. The Notch ligands include classical ligands
such as Jagged –Jag1 and Jag2 -and Delta-like -DLL1, DLL3 and DLL4 -as well as several
atypical ligands DNER, F3/Contactin1, NB-3/Contactin6 and Delta-like 1 homologue.
The Notch pathway is intricately involved in the development of the cardiovascular system. One
of the major functions of Notch signaling is its ability to influence cell fate decisions during
development (Kwon C et al 2005). Several of the Notch pathway components have been linked
to the vascular system development, including Jagged1, Notch1, Notch2, Notch4 and
presenilin(Eiraku M et al 2005 ; Bray S. J et al 2008). It was reported that the Notch ligand and
receptor expression is restricted to either the endothelial or vascular SMC during different stages
of development. This is demonstrated by Notch1, Notch4 and Dll4 which are initially present in
the embryo in all blood cells and is later restricted to arteries. Similarly Notch2 expression is
restricted to the pulmonary artery (Bruckner K et al 2000). The epithelial-mesenchymal
transitions, a potential source of mesenchymal stem cells in the adult vasculature and cardiac
valves, may occur as a result of Notch activation by Jag1, which represses the activation of Wnt
pathway. Preferential expression of Jagged1 in the endothelial cells of injured blood vessels may
induce high levels of Notch receptors in neighboring smooth muscle cells and reduce contact
inhibition and cell adhesion through a reduction in cadherin levels indicating that Jagged1 may
be involved in the de-differentiation of vascular cells and the cellular proliferation phase
characteristic for atherosclerosis (Ivey K. N et al 2008).
It has been reported that constitutive activation of the Notch pathway significantly reduces
cardiac differentiation. The Notch1 receptor is responsible for the blockade of cardiogenesis.
Notch1 also is involved in the suppression of catrdiomyocyte differentiation. It has also been
proposed that inhibition of cardiogenesis by Notch signalling is carried out by blocking
mesodermal differentiation (Sethupathy P. Et al 2006). Hence Notch signaling pathway which is
known to influence cardiogenesis and heart development, in conjunction with miRNAs, needs to
be elucidated.
Notch signalling and miRNA in cardiomyopathy
miRNA regulation is essential for normal Notch signalling. Default repression by miRNAs does
not necessarily have to target core pathway components; it may be equally effective when it
intercepts their transcriptional targets as shown by the default repression of the E (spl) and
Bearded (Brd) gene clusters whose activation is dependent on signalling by Notch in Drosophila.
This is a highly redundant system, in which families of related miRNAs (miR-2, miR-4, miR-7,
miR-11 and miR-79) promiscuously target a family of related mRNAs, preventing aberrant
deployment of Notch-mediated developmental programmes (Sabatel C et al 2011). Regulation of
the expansion of cardiac and muscle progenitor cells is carried out by the notch ligand Delta, and
this is targeted for repression by dmiR-1 (Rao P. K et al 2006 ; Sethupathy P et al 2006 ; Zhao Y
et al 2005). Several conserved putative miR-1-binding sites were found in the 3’-UTR of the
gene encoding Delta (Artavanis-Tsakonas S et al 1999 ; Corbin V et al 1991 ; Heitzler P. &
Simpson P. 1991). It was also found that miR-1 fine-tunes Notch ligand Delta that is critically
involved in differentiation of cardiac and somatic muscle progenitors and targets a pathway
miRNA regulation is essential for normal Notch signalling. Default repression by miRNAs does
not necessarily have to target core pathway components; it may be equally effective when it
intercepts their transcriptional targets as shown by the default repression of the E (spl) and
Bearded (Brd) gene clusters whose activation is dependent on signalling by Notch in Drosophila.
This is a highly redundant system, in which families of related miRNAs (miR-2, miR-4, miR-7,
miR-11 and miR-79) promiscuously target a family of related mRNAs, preventing aberrant
deployment of Notch-mediated developmental programmes (Sabatel C et al 2011). Regulation of
the expansion of cardiac and muscle progenitor cells is carried out by the notch ligand Delta, and
this is targeted for repression by dmiR-1 (Rao P. K et al 2006 ; Sethupathy P et al 2006 ; Zhao Y
et al 2005). Several conserved putative miR-1-binding sites were found in the 3’-UTR of the
gene encoding Delta (Artavanis-Tsakonas S et al 1999 ; Corbin V et al 1991 ; Heitzler P. &
Simpson P. 1991). It was also found that miR-1 fine-tunes Notch ligand Delta that is critically
involved in differentiation of cardiac and somatic muscle progenitors and targets a pathway
essential for progenitor cell specification and asymmetric cell division. Introduction of miR-133
allows cardiac tissue formation, but the tissue is disorganized and does not lead to chamber
formation. It has thus been shown that miR-1 and miR-133 function antagonistically to each
other whenever miR-1 shifts the development of the stem cells towards a cardiac fate and miR133
inhibits this event. The cardiac fate achieved by miR-1 is by transcriptional repression of
Dll-1, which is the mammalian ortholog of Delta in Drosophila(Atsuhiko I et al 2011). It has also
been reported that the members of the Hairy family, particularly Hrt2/Hey2, involved in heart
disease, are themselves regulated by miR-1-2 and members of the Hairy family are
transcriptional repressors which mediate Notch signalling. The effect produced by miR-1-2 on
Hey2 is also seen on Hand1, involved in Notch pathway, which is a bHLH transcription factor
involved in ventricular development and septation that, in combination with Hand2 (a paralog of
Hand1), is known to regulate expansion of the embryonic cardiac ventricles (Kwon C et al 2005 ;
Jiang Q et al 2009 ; Rusconi, J. C. & Corbin, V. 1998 ; Sabatel C et al 2011 ; Sapir A et al 2005).
miR-1-2 appears to be involved in the regulation of diverse cardiac and skeletal muscle
functions, including cellular proliferation, differentiation, cardiomyocyte hypertrophy, cardiac
conduction and arrhythmias (Han Z. & Bodmer R. 2003). Hence miRs regulating the Notch
signaling pathway which is involved in cardiac development, differentiation and ultimately
cardiomyopathy, needs to be evaluated.
Conclusion
In the preceding discussion, the involvement of miRNAs in regulating developmental processes
in the heart and their involvement in cardiomyopathies via sarcomeric genes, modifiers and
In the preceding discussion, the involvement of miRNAs in regulating developmental processes
in the heart and their involvement in cardiomyopathies via sarcomeric genes, modifiers and
signaling pathways such as the Notch pathway is reviewed. Mutations in sarcomeric genes are
the primary causatives of the disease, whereas the modifiers determine the severity.
The miRNAs regulating these genes thus play an important role in development and disease. The
roles played by several miRNAs have been elucidated, but an in depth analysis of the miRNAs,
and the genes that encode them and also the genes targeted by them is essential to bring forward
the complex interplay that occurs during development and disease causation. Notch pathway is
involved in the development of cardiovascular system, as it promotes cell proliferation and
apoptosis. Many miRNA are known to regulate the Notch pathway and the dysregulation of
these miRNA affects cell proliferation, differentiation, cardiac conduction, leading to cardiac
hypertrophy and arrhythmias. But the information available in this context is still obscure.
Further studies are necessary to identify other miRNAs involved in regulation of notch pathway.
A study of miRNAs would also give us potential therapeutic targets in the form of antagomirs
which are used for silencing miRNAs that are implicated in the manifestation of
cardiomyopathies. Complete revelation of the roles played by miRNA may give crucial insights
into many of the mysteries of the human heart.

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