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miRNAs at the heart of the matter.

Wang Z, Luo X, Lu Y, Yang B - J. Mol. Med. (2008)

Bottom Line: The target genes and signaling pathways linking the miRNAs to cardiovascular disease are highlighted.The applications of miRNA interference technologies for manipulating miRNA expression, stability, and function as new strategies for molecular therapy of human disease are evaluated.Finally, some specific issues related to future directions of the research on miRNAs relevant to cardiovascular disease are pinpointed and speculated.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Montreal Heart Institute, Montreal, PQ H1T 1C8, Canada. wz.email@gmail.com

ABSTRACT
Cardiovascular disease is among the main causes of morbidity and mortality in developed countries. The pathological process of the heart is associated with altered expression profile of genes that are important for cardiac function. MicroRNAs (miRNAs) have emerged as one of the central players of gene expression regulation. The implications of miRNAs in the pathological process of cardiovascular system have recently been recognized, representing the most rapidly evolving research field. Here, we summarize and analyze the currently available data from our own laboratory and other groups, providing a comprehensive overview of miRNA function in the heart, including a brief introduction of miRNA biology, expression profile of miRNAs in cardiac tissue, role of miRNAs in cardiac hypertrophy and heart failure, the arrhythmogenic potential of miRNAs, the involvement of miRNAs in vascular angiogenesis, and regulation of cardiomyocyte apoptosis by miRNAs. The target genes and signaling pathways linking the miRNAs to cardiovascular disease are highlighted. The applications of miRNA interference technologies for manipulating miRNA expression, stability, and function as new strategies for molecular therapy of human disease are evaluated. Finally, some specific issues related to future directions of the research on miRNAs relevant to cardiovascular disease are pinpointed and speculated.

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Related in: MedlinePlus

Diagram depicting the miRNAs, along with their target genes, which have been experimentally evidenced for their participation in the development of cardiac hypertrophy. THRAP1 thyroid hormone receptor associated protein 1; RasGAP Ras GTPase-activating protein; Cdk9 cyclin-dependent kinase 9; Rheb Ras homolog enriched in brain; RhoA, a GDP–GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. These proteins have been implicated in hypertrophy
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Fig1: Diagram depicting the miRNAs, along with their target genes, which have been experimentally evidenced for their participation in the development of cardiac hypertrophy. THRAP1 thyroid hormone receptor associated protein 1; RasGAP Ras GTPase-activating protein; Cdk9 cyclin-dependent kinase 9; Rheb Ras homolog enriched in brain; RhoA, a GDP–GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. These proteins have been implicated in hypertrophy

Mentions: The first common finding is that an array of miRNAs is significantly altered in their expression, either upregulated or downregulated, and studies from different research groups demonstrated overlapping miRNAs that are altered in cardiac hypertrophy. The second common finding is that single miRNAs can critically determine the progression of cardiac hypertrophy. Olson's [38] group reported >12 miRNAs that are upregulated or downregulated in cardiac tissue from mice in response to transverse aortic constriction (TAC) or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were found similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs induced hypertrophy in cultured cardiomyocytes. Particularly, overexpression of miR-195 alone, which was upregulated during cardiac hypertrophy, was sufficient to induce pathological cardiac growth and heart failure in transgenic mice. However, the target genes for miR-195 relevant to hypertrophy have not been studied. The same group recently found that miR-208, encoded by an intron of the α-MHC gene, is required for cardiomyocyte hypertrophy, fibrosis, and expression of β-MHC in response to stress and hypothyroidism [32]. The study showed that miR-208 mutant mice failed to undergo stress-induced cardiac remodeling, hypertrophic growth, and β-MHC upregulation, whereas transgenic expression of miR-208 was sufficient to induce β-MHC. miR-208 regulates β-MHC by repressing the thyroid hormone receptor associated protein 1, a cofactor of the thyroid hormone receptor and a predicted miR-208 target mRNA. Abdellatif's [39] group reported an array of miRNAs that are differentially and temporally regulated during cardiac hypertrophy. They found that miR-1 was singularly downregulated as early as day 1, persisting through day 7, after TAC-induced hypertrophy in a mouse model. Overexpression of miR-1 carried by adenovirus vector inhibited its in silico-predicted growth-related targets, including Ras guanosine-triphosphatase-activating protein, cyclin-dependent kinase 9, fibronectin, and Ras homolog enriched in brain, in addition to protein synthesis and cell size. Their study also suggests that miRNA expression profiles at different time points after TAC are different, with expression of >50 miRNAs progressively changing during development of pressure overload cardiac hypertrophy. Thus, they proposed that miRNAs play an essential regulatory role in the development of cardiac hypertrophy, wherein downregulation of miR-1 is necessary for the relief of growth-related target genes from its repressive influence and induction of hypertrophy. A study from Condorelli's group focuses on the role of miR-133 and miR-1 in cardiac hypertrophy with three murine models: TAC mice, transgenic mice with selective cardiac overexpression of a constitutively active mutant of the Akt kinase, and human tissues from patients with cardiac hypertrophy [40]. They first showed that cardiac hypertrophy in all three models resulted in reduced expression levels of both miR-133 and miR-1 in the left ventricle. They then described that in vitro overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In contrast, suppression of miR-133 induced hypertrophy, which was more pronounced than that after stimulation with conventional inducers of hypertrophy. In vivo inhibition of miR-133 by a single infusion of an antimiRNA antisense oligonucleotide (AMO) against miR-133 caused marked and sustained cardiac hypertrophy. They then identified specific targets of miR-133: RhoA, a guanosine diphosphate–guanosine triphosphate exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase implicated in hypertrophy; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. Cheng et al. [41] identified 19 deregulated miRNAs in hypertrophic mouse hearts after aortic banding. Knockdown of miR-21 expression via AMO-mediated depletion had a significant negative effect on cardiomyocyte hypertrophy induced by TAC in mice or by angiotensin II or phenylephrine in cultured neonatal cardiomyocytes. Consistently, another independent group identified 17 miRNAs upregulated and three miRNAs downregulated in TAC mice and seven upregulated and four downregulated in phenylephrine-induced hypertrophy of neonatal cardiomyocytes. They further showed that inhibition of endogenous miR-21 or miR-18b that are most robustly upregulated augments hypertrophic growth, while introduction of either of these two miRNAs into cardiomyocytes represses cardiomyocyte hypertrophy [42]. A study directed to the human heart identified 67 significantly upregulated miRNAs and 43 significantly downregulated miRNAs in failing left ventricles versus normal hearts [43]. Interestingly, 86.6% of induced miRNAs and 83.7% of repressed miRNAs were regulated in the same direction in fetal and failing heart tissue compared with healthy hearts, consistent with the activation of “fetal” cardiac genes in heart failure. Bioinformatics analysis revealed that the mRNAs upregulated in the failing heart contain the putative binding sites for the downregulated miRNAs and vice versa. Most strikingly, transfection of cardiomyocytes with a set of fetal miRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart. The above findings are summarized in Fig. 1.Fig. 1


miRNAs at the heart of the matter.

Wang Z, Luo X, Lu Y, Yang B - J. Mol. Med. (2008)

Diagram depicting the miRNAs, along with their target genes, which have been experimentally evidenced for their participation in the development of cardiac hypertrophy. THRAP1 thyroid hormone receptor associated protein 1; RasGAP Ras GTPase-activating protein; Cdk9 cyclin-dependent kinase 9; Rheb Ras homolog enriched in brain; RhoA, a GDP–GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. These proteins have been implicated in hypertrophy
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2480593&req=5

Fig1: Diagram depicting the miRNAs, along with their target genes, which have been experimentally evidenced for their participation in the development of cardiac hypertrophy. THRAP1 thyroid hormone receptor associated protein 1; RasGAP Ras GTPase-activating protein; Cdk9 cyclin-dependent kinase 9; Rheb Ras homolog enriched in brain; RhoA, a GDP–GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. These proteins have been implicated in hypertrophy
Mentions: The first common finding is that an array of miRNAs is significantly altered in their expression, either upregulated or downregulated, and studies from different research groups demonstrated overlapping miRNAs that are altered in cardiac hypertrophy. The second common finding is that single miRNAs can critically determine the progression of cardiac hypertrophy. Olson's [38] group reported >12 miRNAs that are upregulated or downregulated in cardiac tissue from mice in response to transverse aortic constriction (TAC) or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were found similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs induced hypertrophy in cultured cardiomyocytes. Particularly, overexpression of miR-195 alone, which was upregulated during cardiac hypertrophy, was sufficient to induce pathological cardiac growth and heart failure in transgenic mice. However, the target genes for miR-195 relevant to hypertrophy have not been studied. The same group recently found that miR-208, encoded by an intron of the α-MHC gene, is required for cardiomyocyte hypertrophy, fibrosis, and expression of β-MHC in response to stress and hypothyroidism [32]. The study showed that miR-208 mutant mice failed to undergo stress-induced cardiac remodeling, hypertrophic growth, and β-MHC upregulation, whereas transgenic expression of miR-208 was sufficient to induce β-MHC. miR-208 regulates β-MHC by repressing the thyroid hormone receptor associated protein 1, a cofactor of the thyroid hormone receptor and a predicted miR-208 target mRNA. Abdellatif's [39] group reported an array of miRNAs that are differentially and temporally regulated during cardiac hypertrophy. They found that miR-1 was singularly downregulated as early as day 1, persisting through day 7, after TAC-induced hypertrophy in a mouse model. Overexpression of miR-1 carried by adenovirus vector inhibited its in silico-predicted growth-related targets, including Ras guanosine-triphosphatase-activating protein, cyclin-dependent kinase 9, fibronectin, and Ras homolog enriched in brain, in addition to protein synthesis and cell size. Their study also suggests that miRNA expression profiles at different time points after TAC are different, with expression of >50 miRNAs progressively changing during development of pressure overload cardiac hypertrophy. Thus, they proposed that miRNAs play an essential regulatory role in the development of cardiac hypertrophy, wherein downregulation of miR-1 is necessary for the relief of growth-related target genes from its repressive influence and induction of hypertrophy. A study from Condorelli's group focuses on the role of miR-133 and miR-1 in cardiac hypertrophy with three murine models: TAC mice, transgenic mice with selective cardiac overexpression of a constitutively active mutant of the Akt kinase, and human tissues from patients with cardiac hypertrophy [40]. They first showed that cardiac hypertrophy in all three models resulted in reduced expression levels of both miR-133 and miR-1 in the left ventricle. They then described that in vitro overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In contrast, suppression of miR-133 induced hypertrophy, which was more pronounced than that after stimulation with conventional inducers of hypertrophy. In vivo inhibition of miR-133 by a single infusion of an antimiRNA antisense oligonucleotide (AMO) against miR-133 caused marked and sustained cardiac hypertrophy. They then identified specific targets of miR-133: RhoA, a guanosine diphosphate–guanosine triphosphate exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase implicated in hypertrophy; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. Cheng et al. [41] identified 19 deregulated miRNAs in hypertrophic mouse hearts after aortic banding. Knockdown of miR-21 expression via AMO-mediated depletion had a significant negative effect on cardiomyocyte hypertrophy induced by TAC in mice or by angiotensin II or phenylephrine in cultured neonatal cardiomyocytes. Consistently, another independent group identified 17 miRNAs upregulated and three miRNAs downregulated in TAC mice and seven upregulated and four downregulated in phenylephrine-induced hypertrophy of neonatal cardiomyocytes. They further showed that inhibition of endogenous miR-21 or miR-18b that are most robustly upregulated augments hypertrophic growth, while introduction of either of these two miRNAs into cardiomyocytes represses cardiomyocyte hypertrophy [42]. A study directed to the human heart identified 67 significantly upregulated miRNAs and 43 significantly downregulated miRNAs in failing left ventricles versus normal hearts [43]. Interestingly, 86.6% of induced miRNAs and 83.7% of repressed miRNAs were regulated in the same direction in fetal and failing heart tissue compared with healthy hearts, consistent with the activation of “fetal” cardiac genes in heart failure. Bioinformatics analysis revealed that the mRNAs upregulated in the failing heart contain the putative binding sites for the downregulated miRNAs and vice versa. Most strikingly, transfection of cardiomyocytes with a set of fetal miRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart. The above findings are summarized in Fig. 1.Fig. 1

Bottom Line: The target genes and signaling pathways linking the miRNAs to cardiovascular disease are highlighted.The applications of miRNA interference technologies for manipulating miRNA expression, stability, and function as new strategies for molecular therapy of human disease are evaluated.Finally, some specific issues related to future directions of the research on miRNAs relevant to cardiovascular disease are pinpointed and speculated.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Montreal Heart Institute, Montreal, PQ H1T 1C8, Canada. wz.email@gmail.com

ABSTRACT
Cardiovascular disease is among the main causes of morbidity and mortality in developed countries. The pathological process of the heart is associated with altered expression profile of genes that are important for cardiac function. MicroRNAs (miRNAs) have emerged as one of the central players of gene expression regulation. The implications of miRNAs in the pathological process of cardiovascular system have recently been recognized, representing the most rapidly evolving research field. Here, we summarize and analyze the currently available data from our own laboratory and other groups, providing a comprehensive overview of miRNA function in the heart, including a brief introduction of miRNA biology, expression profile of miRNAs in cardiac tissue, role of miRNAs in cardiac hypertrophy and heart failure, the arrhythmogenic potential of miRNAs, the involvement of miRNAs in vascular angiogenesis, and regulation of cardiomyocyte apoptosis by miRNAs. The target genes and signaling pathways linking the miRNAs to cardiovascular disease are highlighted. The applications of miRNA interference technologies for manipulating miRNA expression, stability, and function as new strategies for molecular therapy of human disease are evaluated. Finally, some specific issues related to future directions of the research on miRNAs relevant to cardiovascular disease are pinpointed and speculated.

Show MeSH
Related in: MedlinePlus