it is well established that the transition of vascular smooth muscle cells ( vsmcs ) from a differentiated phenotype to a dedifferentiated state plays a critical role in the pathogenesis of atherosclerosis .
the phenotypic modulation in vsmcs is accompanied by accelerated migration , proliferation and production of extracellular matrix components .
eventually , these cellular events result in the formation of atherosclerotic lesions . however , the molecular mechanisms involved in phenotypic control are still unclear
. micrornas ( mirnas ) are a class of endogenous , small , non - coding rnas that pair with sites can in 3 ' untranslated regions in mrnas of protein - coding genes to downregulate their expression .
more importantly , one mirna is able to regulate the expression of multiple genes because it can bind to its mrna targets as either an imperfect or a perfect complement .
thus , a mirna can be functionally as important as a transcription factor . as a group , mirnas
it is therefore not surprising that mirnas are involved in the regulation of all major cellular functions .
recently , the role of mirnas in cardiac cell differentiation has been described . in this study , kwon et al . demonstrated that mir-1 plays important roles in modulating cardiogenesis and in maintenance of muscle - gene expression by targeting transcripts encoding the notch ligand delta .
the biological roles of mir-145 in diverse cancer cells have been recently identified ( reviewed in ) . in a recent article reported by xu et al .
, mir-145 was found to be a critical switch for embryonic stem cell differentiation by repressing some core pluripotency factors . whether mirnas participate in the phenotypic control of vsmcs was unknown until recently . in this respect ,
three independent groups have reported exciting new discoveries regarding the critical role of the vsmc - enriched mirna , mir-145 , in vsmc phenotypic modulation [ 8 - 10 ] .
they identified that mir-145 plays a role not only in the differentiation of multipotent neural crest stem cells into vsmcs , but also in the differentiation of adult vsmcs .
other mirnas that may participate in the phenotypic modula tion of vsmcs are mir-143 and mir-221 [ 9 - 12 ] .
this minireview summarizes the current research progress regarding the roles of mir-145 in the vsmc phenotype and the potential therapeutic opportunities of mirnas in atherosclerotic vascular disease .
ji et al .   demonstrated that mir-145 is the most abundant mirna in arteries . its expression is significantly downregulated in rat balloon - injured arteries with neointimal lesion growth .
a recent nature article by cordes et al .   showed that mir-145 expression was also decreased in mouse carotid arteries after ligation injury .
more interestingly , transcripts of mir-145 were down regulated to nearly undetectable levels in atherosclerotic lesions containing neointimal hyperplasia .
our own unpublished data also revealed that mir-145 is largely downregulated in atherosclerotic mouse and human arteries , although the downregulation is less pronounced compared with that from cordes ' study .
if the selected atherosclerotic tissue had fewer vsmcs , the expression level of mir-145 could be lower .
recently , cheng et al .   found that mir-145 is the most abundant mirna in differentiated vsmcs .
also , its expression is quickly downregulated in subcultured dedifferentiated vsmcs and in dedifferentiated vsmcs induced by stimulation with platelet - derived growth factor ( pdgf ) .
our unpublished data also indicate that mir-145 expression in vsmcs isolated from balloon - injured rat carotid arteries and atherosclerotic apoe - knockout mouse aortas is significantly decreased compared with that in vsmcs isolated from normal control arteries .
.   found that , during the development of arteries , the expression of mir-145 is associated with the state of vsmc differentiation .
mir-145 expression is notably absent in the aorta and pulmonary arteries during later cardiogenesis , during which vsmcs and arteries are developing .
in contrast , high transcript levels of mir-145 in vsmcs of the arteries are demonstrated postnatally , after vsmcs and arteries have completed their development .
cordes et al .   demonstrated that mir-145 was necessary and sufficient to induce differentiation of multipotent neural crest stem cells into vsmcs .
in addition , cheng et al .   identified for the first time that mir-145 is a critical modulator for the vsmc phenotype both in vitro and in vivo .
vsmc differentiation marker genes such as sm -actin , calponin , and sm - mhc were downregulated by mir-145 downregulation , and upregulated by mir-145 upregulation . the regulatory effect of mir-145 on the vsmc phenotype
was further verified by cordes and colleagues . in contrast , another co - expressed mirna , mir-143 , had no significant effect on marker genes for vsmc differentiation , although it had a strong effect on vsmc proliferation .
.   demonstrated that the expres sion of the mir-143/145 cluster is confined to vsmcs during development .
they found that mir-143 and mir-145 are required for vsmc acquisition of the contractile phenotype because the vsmcs from mir-143/145-deficient mice are locked in the synthetic state .
the regulatory effects of mirnas on the vsmc phenotype are not limited to mir-143 and mir-145 .
two recent studies revealed that mir-221 is also related to the vsmc phenotype that affects vsmc proliferation and migration .
it is well known that phenotypic modulation of vsmcs is an initial cellular event in the development of atherosclerotic vascular disease . to determine the therapeutic potential of mir-145 in vascular disease ,
.   demonstrated that restoration of mir-145 in rat balloon - injured carotid arteries via adenovirus - mediated gene transfer significantly inhibited neointimal lesion growth .
in contrast , knockout of mir-143 and mir-145 resulted in the formation of neointima in mouse arteries .
the roles of mir-145 in the vsmc phenotype and atherosclerotic vascular disease are summarized in figure 1 .
expression modulation of mir-145 in the vascular walls and the potential roles of mir-145 in vascular smooth muscle cell phenotype and atherosclerosis .
its expression is significantly downregulated in developing arteries and in adult arteries containing intimal hyperplasia .
the downregulated mir-145 in adult arteries will increase vsmc dedifferentiation and result in the development of atherosclerotic lesions .
mirna - based therapy may have some advantages compared with that for other molecular targets because one endogenous mirna can target its multiple target genes .
although the recent studies have demonstrated that targeting mirnas , and mir-145 in particular , may represent a new therapy for atherosclerosis , there is still a long road before mirna - based technology can be translated to clinical therapy .
first , the critical mirnas responsible for the development of atherosclerosis must be further identified , especially in human atherosclerotic arteries .
second , the detailed cellular and molecular mechanisms of these critical mirnas in the prevention and treatment of atherosclerosis should be studied .
third , in addition to the biological effects of these mirnas on vsmcs , their effects on other atherosclerosis - related cellular events should be identified .
fourth , although methods are available to downregulate a mirna in vivo , technology for upregulating a mirna in the vascular walls in vivo requires development . finally , the potential side - effects of mirna - based therapy should be studied before application in the clinic .
mirna : microrna ; mir-145 : microrna-145 ; pdgf : platelet - derived growth factor ; vsmc : vascular smooth muscle cell .
this work was supported by a national institutes of health grant hl080133 and a grant from the american heart association 09grnt2250567 .
 micrornas ( mirnas ) represent a class of small , non - coding rnas that negatively regulate gene expression via degradation or translational inhibition of their target mrnas . 
 recent studies have identified that mir-145 is the most abundant mirna in normal arteries and vascular smooth muscle cells ( vsmcs ) , and its expression is significantly downregulated in dediffer - entiated vsmcs and atherosclerotic arteries . 
 mir-145 plays a critical role in modulating vsmc phenotype . 
 because phenotypic modulation of vsmcs is an initial cellular event in the development of atherosclerosis , mirnas , and mir-145 in particular , may represent new therapeutic targets for atherosclerosis . 