The Role of microRNAs in Cardiovascular Disease

IJMCM Spring 2013, Vol 2, No 2 Review Article The Role of MicroRNAs in Cardiovascular Disease Sarah Sadat Aghabozorg Afjeh, Sayyed Mohammad Hossein Ghaderian∗ Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Submmited 10 March 2013; Accepted 29 May 2013 Cardiovascular disease has become the main factor of death and birth defects in the world. There are some therapeutic structures and drugs for curative and palliative therapy of the disease, but to the aim of accessing reliable therapy or to postpone onset of disease, especially for individuals with heritable coronary artery disease in their pedigree Genetic engineering technologies are making advances in the field by identifying oligonucleotides with higher potencies which can be easily targeted against almost any gene, particularly interfering RNA (RNAi). Recently, the focus of RNAi approaches has encompassed the use of synthetic sequences to mimic or silence endogenous microRNAs (miRNAs) that are abruptly dysregulated following cardiovascular diseases. In this review, we summarize the role of miRNAs in heart development and vascular system as two main factors of birth defects and adult morbidity and mortality and miRNAS as new therapeutic agents. Key words: microRNA, cardiovascular disease C ardiovascular disease, including its most factors and genetic risk factors. To elucidate the severe complication myocardial infarction, determinants of cardiovascular disease, many has become the main factor of death in the world epidemiological studies have focused on the (1, 2). behavioral and lifestyle determinants of these risk More than 80% of sudden cardiac deaths in factors, whereas, others have examined whether the world are caused by atherosclerotic coronary specific candidate genes influence quantitative artery disease (CAD), and the remaining 20% of variation in these phenotypes (3). There are two cases are caused by other diseases including separated environmental factors which lead to the cardiomyopathies, congenital heart disease, left disease, including habitual factors like smoking or ventricular hypertrophy, aortic valve disease, and other lifestyles, and epidemiological factors or other cardiac disorders. The familial aggregation of factors related with the place an individual lives coronary heart disease can be in large part like air pollution and other environmental factors. accounted for by a clustering of cardiovascular Many authors have examined the association of disease risk factors separated by environmental risk height, weight, body mass index (BMI), cholesterol ∗ Corresponding author: Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E. Mail: sghaderian@yahoo.co.uk Aghabozorg Afjeh SS et al. level, and pulse rate with blood pressure synthetic sequences to mimic or silence endogenous phenotypes as environmental factors and all the miRNAs that are abruptly dysregulated following traits have shown a significant association (4, 5). As cardiovascular mentioned before there are also genetic risk factors miRNAs in the pathological process of the causing cardiovascular disease. Despite years of cardiovascular intensive research, not a single genetic risk factor is recognized, and research on miRNAs in relation to used for risk assessment. The new strategy of cardiovascular disease has now become a rapidly genome-wide association (GWA) studies (for evolving field (10). example, see http://www.wtccc. org.uk/) is starting Biology of miRNA diseases. system The have implications recently of been to reveal novel genetic factors that contribute to Epigenetic control mechanisms including disease risk. The spectrum of the genetic variants DNA methylation, histone modification, and non that predispose to CVD spans from rare, highly coding RNAs as well as differential RNA splicing, deleterious mutations responsible for Mendelian play a key role in the regulation of tissue diseases which are usually identified by linkage homeostasis and disease development and enable studies, to common polymorphisms (minor allele the cell to respond quickly to environmental frequency >1%) that, alone or in combination, changes (11, 12). Noncoding RNAs are functional modulate the risk of the disease. Because complex RNA molecules that belong to several groups and diseases do not follow a clear pattern of Mendelian are involved in many cellular processes. miRNAs inheritance, the strategy used to identify their genes are a class of short, ~22-nucleotide, double strand of predisposition is usually not based on family non-coding studies but on a radically different approach called transcribed and control gene expression by either “genetic association” analysis (6). Also, in the case inducing of complex diseases such as myocardial infarction translation. The first evidence that double strand (MI), linkage analysis is compounded by genetic RNA (dsRNA) could achieve efficient gene heterogeneity of this disease and many other silencing through miRNAs came from the studies of factors, including incomplete penetrance of disease- lineage causing genes interaction with environmental developmental timing in the nematode C. elegans in factors, the high prevalence of the disease-causing 1993 allele in the population, and late onset of disease melanogaster have contributed toward under- (7). According to researches based on Meta- standing the biochemical nature of the miRNA analysis technique published on 2011, specific pathway. RNAs mRNA mutant (13). that are degradation named Further lin-4, analyses endogenously or blocking which in affect Drosophila genetic loci were introduced to be related with miRNA genes are transcribed by RNA cardiovascular disease and more specifically with polymerase II to yield pre-miRNA transcripts that MI. Expression changes in some of them cause are then processed by the nuclear enzymes Drosha increasing risk of MI (8, 9). (14). The resulting 70 mer transcript is folded into a Regarding these loci as important genetic risk factors for the disease, endogenous micro stem loop structure that is then exported into the cytoplasm by the shuttling factor Exportin 5 (15). RNAs (miRNAs) can be considered as factors The cytoplasmic enzyme Dicer, a member of involved in cardiac disease by their role in the class III RNA endonuclease, is then required to regulating the genes expression. process pre-miRNAs into double-stranded mature Recently, the focus of interfering RNA ~19–25 nt, miRNA generating 2 nucleotide (RNAi) approaches has encompassed the use of overhangs at the 3’ termini. These miRNAs are Int J Mol Cell Med Spring 2013; Vol 2 No 2 51 The Role of MicroRNAs in Cardiovascular Disease recognized and bound by a multi-protein complex cell types and were reported to participate in the called the RNA-induced silencing complex (RISC) specification of cell identity (31). (16). Some experiments with different approaches Each miRNA duplex is formed by a guide demonstrated the role of miRNAs during vertebrate strand and a passenger strand. An enzyme within development. One of these approaches and also the the RISC, the endonuclease Argonaute 2 (Ago 2) first evidence for a regulation of endothelial cell catalyzes the unwinding of the miRNA duplex. functions by miRs came from the studies in which Once unwound, the guide strand is incorporated the first and second exons of the Dicer, miRNA into the RISC, while the passenger strand is processing enzyme encoding gene, were deleted released. RISC uses the guide strand to find the using creatine kinase (Cre) recombinase expressed mRNA that has a complementary sequence leading under the control of endogenous Nkx2.5 (one of the to the endonucleolytic cleavage of the target earliest cardiac markers, during mouse and human miRNA (17). embryonic stem cells differentiation) regulator miRNAs in Cardiovascular Disease elements, which have been reported to lead to Recent studies have shown that miRNAs embryonic lethality in mice at embryonic stage, play an essential role in some biological processes between days 12.5 and 14.5 of gestation (32, 33), such as cell proliferation or cell differentiation, and due to either a loss of pluripotent stem cells (34) or apoptosis. Also, they are associated with important disrupt angiogenesis in the embryo (33). Also, adult diseases including cancer mice without Dicer genes in the myocardium has and cardiovascular diseases (18-20). been shown to have a high incidence of sudden According to Sanger institute and miRNA death, cardiac hypertrophy and reactivation of the databases (21, 22) more than 1500 miRNAs have fetal cardiac gene program (35). been identified in humans, current databases report Moreover, blood vessel formation/maintenance in 1600 precursors and 2042 mature miR sequences embryos and yolk sacs was severely compromised for humans (22). Among them, a subset of miRNAs and the expression of VEGF, FLT1, KDR, and including miR-1, miR-133, miR-206 and miR-208 TIE1 was altered in the mutant embryos indicating are muscle tissue-specific, and have been called an essential role of Dicer for embryonic blood myomiRs (23-26). vessel development (11, 33). Also, there are many miRNAs which Rao et al. used muscle creatine kinase participate in cardiac related diseases and their (MCK)-Cre mice system to perform studies on mice changes can be considered as a biomarker for the with a muscle-specific deletion of the DiGeorge disease. In this review, we summarize the role of syndrome critical region gene 8 (DGCR8), which is miRs in heart development and vascular system as required for the production of all canonical miRs. two main factors of birth defects and adult Since endogenous MCK expression reportedly morbidity and mortality (27-30). peaks around birth and declines to 40 % of peak miRNA and cardiac development levels by day 10, and the phenotypic outcome was Several accurate and complex interactions similar to the cardiac-specific dicer deficient mice, among variants of cell types from several lineages, it seems that miRNAs play an important role in cardiomyocytes, maintaining cardiac function in mature cardio- endocardial, epicardial and vascular cells, fibroblasts and cells of the conduc- myocytes (32). tion system, are required for heart formation. Many Since there are different reports about the specific miRNAs are enriched in different cardiac role of miRNAs in adult heart, further studies are 52 Int J Mol Cell Med Spring 2013; Vol 2 No 2 Aghabozorg Afjeh SS et al. required in this filed. 133, which was transcribed together with miR-1 as Muscle-specific mirRNAs miR-1 and miR- a bicistronic cluster, was decreased in the left 133, as conserved miRNAs which are derived from ventricle of the above mentioned three hypertrophic common during models (42). Mice lacking either miR-133a-1 or development and in adults, and were among the miR-133a-2 that survive to adult, suffer from first miRs that had been identified as major dilated cardiomyopathy and succumb to heart regulators of muscle lineage commitment and had failure. precursor, play their role critical role in regulating muscle proliferation and differentiation (11). These experiments prove the important role of miRNAs for the development of the organ. The Studies based on deep sequencing of a small heart as a particularly informative model for such RNA library reported that miRNA (miR)-1 was organ patterning, has numerous transcriptional quite enriched and accounted for nearly 40% of all networks that establish chamber-specific gene known miRNAs in the adult heart (32). The miR-1 expression and function (32, 43). miRNA precursor is a small micro RNA that miRNAs in Vascular system and angiogenesis regulates its target protein's expression in the cell. The vascular system is fundamental for In humans, there are two distinct miRNAs that embryonic development and adult life, and aberrant share an identical mature sequence, these are called vascularization miR-1-1 and miR-1-2 which target the same diseases, including cancer, atherosclerosis and sequences and it has also been shown that in miR- stroke. Vascular system needs the establishment 1-2-deficient mice with miR-1-1 expression, there and remodeling of a contiguous series of lumenized are spectrum of abnormalities, including ventricular tubes made of endothelial cells for its formation and septal defects in a subset that suffer early lethality, function (31). is associated with numerous cardiac rhythm disturbances in those that survive New studies indicated that miRNAs are (32) and functional defects in regulation of cardiac highly expressed in vasculature and are critical morphogenesis, electrical conduction, and cell modulators cycle control (36). Studies showed that miR-1 contraction, migration, apoptosis, and dysregulation regulates of their expression can cause vessel diseases (44). cardiac differentiation (36-39) and controls heart development in mice by regulation of the cardiac transcription factor Hand2 (32). Also, miR-1 is downregulated in myocardial for vascular cell differentiation, Recently, a few specific miRNAs that regulate endothelial cell functions and angiogenesis have been described (31) which are described. infarcted tissue compared to healthy heart tissue One of the new studied miRNAs in this field and Plasma levels of miR-1 can be used as a is miR-126 which is known as an angiogenesis sensitive biomarker for myocardial infarction (40). regulator in development and neoangiogenesis after Although miR-1 and miR-133 are co- myocardial infarction and positively regulates transcribed, their function appears clearly distinct. angiogenesis through multiple signaling pathways miR-133a double mutant mice are normal, whereas, (45). The endothelial-cell-specific miR-126 is the deletion of both miR-133a genes causes late found on chromosome 9 within intron 7 of the embryonic or neonatal lethality due to ventricular epidermal septal defects in approximately half of the double- multiple 7 (EGFL7) gene in the human genome. mutant embryos or neonates and abnormalities in EGFL7 is secreted by endothelium and regulates cardiomyocyte proliferation (32, 41). angiogenesis and encodes an endothelial-cell- Caré et al, found that the expression of miR- growth factor (EGF)-like-domain, enriched growth factor involved in the control of Int J Mol Cell Med Spring 2013; Vol 2 No 2 53 The Role of MicroRNAs in Cardiovascular Disease cell migration (46). Blood flow can induce miR-126 several regulators of actin signalling, including Rho to stimulate vascular endothelial growth factor GTPases, sling -shot homologue 2, adducin, cofilin signaling and controlling angiogenesis of aortic and actin itself (56). According to Elia et al. miR- arch vessels (47). miR-126 represses the actions of 143 has higher expression in heart than in other the Sprouty-related protein, SPRED1, and phospho- organs and is expressed in lung, skeletal muscle, inositol-3 kinase regulatory subunit 2, both negative heart, and skin and is most abundant in aorta and regulators of VEGF signals. Lack of miR-126 in fat, where miR-145 is also at its highest expression mice cause leaky vessels and defects in angio- level (53, 57). genesis but does not cause mortality (48, 49). Creating genetic mutation in miR-143/145 in Antisense-oligonucleotide-mediated knock- vivo proved that these miRNAs are unessential for down of miR-126 in zebrafish causes complete smooth muscle specification, but they are required embryonic lethality owing to the loss of vascular for switching proliferative and contractile VSMC integrity and hemorrhaging (50). phenotypes to each other. Experiments demons- One other miRNA which plays a role in trated that because of their destabilizing effect on angiogenesis is miR-21. PTEN and Bcl-2, two transcripts encoding the repressor of the contractile important signal molecules associated with vascular VSMC phenotype, including klf4, klf5 and Ace, in smooth and vivo, mice lacking miR-143/145 display reduced apoptosis, are the targets of miR-21, through which arterial medial thickness, decreased vascular tone miR-21 exerts its function (51). Overexpression of and reduced systemic blood pressure during this miRNA induces high expression of HIF-1alpha homeostasis (58). muscle cells (VSMCs) growth and VEGF, both of which promote angiogenesis. Also, Human Genome Wide Association Indeed, cells transfected with miR-21 induced more studies have identified SNPs in the miRNA branching binding sites of several RAAS (renin-angiotensin of micro vessels in the Chick Chorioallantoic Membrane (CAM) assay (52). aldosterone system)-associated genes that correlate Apart from their role in angiogenesis and its with a dysregulation of blood pressure (58). promotion, miRNAs have other roles in vascular The renin-angiotensin aldosterone system is a system. VSMCs are able to perform both contractile hormonal and synthetic functions, which are associated with arterial pressure, tissue perfusion, and extracellular changes in morphology, proliferation and migration volume (59). cascade that functions to control rates and are characterized by the specific Another mirRNA that we discuss in this expression of different marker proteins. Several review is miR-451. Studies have demonstrated that miRNAs, including miR-143 and miR-145 have a the highly conserved miR, miR-451, is expressed demonstrated role in VSMC differentiation (53). extensively in endothelial and blood cell lineages miR-143 and miR-145 encoding genes are during embryogenesis and has distinct functions highly conserved and lie in close proximity with during in vitro embryonic stem cell differentiation each other on human chromosome 5 (54, 55). by promoting the differentiation of endothelial and Studies based on northern blotting indicated that the blood cells while blocking the differentiation of highly conserved miR-143/145 encoding genes are cardiomyocytes. This function is achieved at least expressed in various mouse tissues and specifically partially through the down regulation of target in smooth muscle cells (SMCs) under the control of Acvr2a and up regulation of Wnt signaling (60). serum response factor (SRF) and members of the Pharmacological knockdown of miR-451, results in myocardin family of co-activators (31) and target reduced baseline hematocrit levels and impaired 54 Int J Mol Cell Med Spring 2013; Vol 2 No 2 Aghabozorg Afjeh SS et al. erythroid expansion in response to oxidative stress biomarkers and understand disease processes. (61-63). Among these miRNAs, some of them were miRNAs as therapeutic agents recognized as the key elements in processing of There are some therapeutic structures and CAD such as miR-126, miR-21, miR-143 and miR- drugs for curative and palliative therapy of the 145. Thus, the next researches should be focused on disease, but to the aim of accessing reliable therapy the accuracy of the miRNAs as biomarker in CAD. or to postpone the onset of disease, especially for people with heritable coronary artery disease in Conflict of interest: Non declared. their pedigree. Genetic engineering technologies are making advances in the field by continually References identifying oligonucleotides with higher potencies, 1. Musunuru K, Kathiresan S. Genetics of coronary artery particularly interfering RNA (miRNA); more disease. Annu Rev Genomics Hum Genet 2010;11:91-108. effective cellular targets, typically in signaling 2. Donyavi T, Naieni KH, Nedjat S, et al. Socioeconomic status pathways; and delivery approaches with the next and mortality after acute myocardial infarction: a study from generation of drug platforms (64). The presence of Iran. Int J Equity Health 2011;10:9. cell-free miRNAs has been detected in a range of 3. 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