miRNA regulation during cardiac development and remodeling in cardiomyopathy (original) (raw)
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MicroRNAs: novel regulators in cardiac development and disease
Cardiovascular Research, 2008
MicroRNAs (miRNAs) are endogenous, small ribonucleotides regulating the translation of target messenger RNAs that have been shown to be involved in orchestrating growth, development, function, and stress responses of various organs, including the heart. Muscle miRNAs are mainly controlled by a network of myogenic transcription factors, and throughout cardiac development they fine-tune regulatory protein levels in a spatiotemporal manner. Recent profiling studies revealed that miRNA expression patterns are derailed in both human cardiac disease and animal models of cardiac hypertrophy and failure. Modulation of miRNA expression in vitro as well as in vivo has revealed an important role of miRNAs in regulating heart function, particularly cardiac growth and conductance. Here, we overview the recent findings on miRNAs in cardiac development and disease and report the latest advances in the identification and validation of miRNA targets, which are important for a comprehensive understanding of cardiac miRNA function. Finally, we focus on the development and use of miRNA antagonists (antagomirs) to target miRNAs in vivo, which may translate into novel therapeutic strategies for heart disease in the future.
Applications of miRNAs in cardiac development, disease progression and regeneration
Stem Cell Research & Therapy
Development of the complex human heart is tightly regulated at multiple levels, maintaining multipotency and proliferative state in the embryonic cardiovascular progenitors and thereafter suppressing progenitor characteristics to allow for terminal differentiation and maturation. Small regulatory microRNAs (miRNAs) are at the level of post-transcriptional gene suppressors, which enhance the degradation or decay of their target protein-coding mRNAs. These miRNAs are known to play roles in a large number of biological events, cardiovascular development being no exception. A number of critical cardiac-specific miRNAs have been identified, of which structural developmental defects have been linked to dysregulation of miRNAs in the proliferating cardiac stem cells. These miRNAs present in the stem cell niche are lost when the cardiac progenitors terminally differentiate, resulting in the postnatal mitotic arrest of the heart. Therapeutic applications of these miRNAs extend to the realm o...
Science Insights, 2019
Cardiac hypertrophy is a frequent pathological reaction to hypertension, pulmonary hypertension, and other cardiovascular diseases. A typical feature of myo-cardial remodeling, cardiac hypertrophy can lead to heart failure and ultimately death. In recent years, studies have found some factors circulating within the blood of young mice can improve symptoms of heart hypertrophy in aged mice. GDF11 in the blood was once considered a key factor to extenuate cardiac hyper-trophy, but subsequent studies question this conclusion. Recent genomic advances have revealed that non-coding RNA, including circular RNA, piRNAs, mi-croRNAs and long non-coding RNAs, play an important role in gene expression and regulation, directly affecting pathophysiological mechanisms. The involvement of microRNAs within the myocardium and aortic valve in the regulation of pathophysiology may lead to the development of cardiovascular disease. Exosome-derived microRNA molecules in the heart are related to heart hyper-trophy and failure. This article reviews the relevance of microRNAs to heart hy-pertrophy and the transported mechanism, which is helpful to discover new therapy and biomarkers for cardiac hypertrophy.■
Cardiac injections of AntagomiRs as a novel tool for knockdown of miRNAs during heart development
Developmental Biology
Background: Studying microRNA networks during heart development is essential to obtain a better understanding of developmental defects and diseases associated with the heart and to identify novel opportunities for therapeutics. Here we highlight the advantages of chicken embryos as a vertebrate model for studying intermediate processes of heart development. Avians develop a four-chambered heart closely resembling human anatomy and they develop ex utero, which makes them easily accessible. Furthermore, embryos are available all year with a steady supply. Results: In this report we established a novel method for the knockdown of microRNA function by microinjecting AntagomiRs into the chicken heart in ovo. Our approach enables the targeted delivery of antagomirs into a locally restricted area and is not impacted by circulation. After further embryo development the successful miRNA knockdown was confirmed. Loss of function phenotypes can be evaluated rapidly, compared to more time-consuming genetic ablation experiments. The local application avoids potential systemic effects of microRNA knockdown, therefore allowing the assessment of impacts on heart development only. The method can be adjusted for different stages of chicken embryos (HH13-HH18) as well as for knockdown or targeted overexpression of coding genes. Conclusion: In conclusion our method allows targeted and locally restricted delivery of Antagomirs to the heart leading to successful knockdown of microRNA function. This method enables rapid phenotypic assessment, for example by gene expression analysis of multiple cardiac genes.
microRNA Perspective on Cardiomyocyte Development and Cardiovascular Diseases
2018
Study of micro-RNA regulatory networks (known as miRNA’s or miR’s), during development and in known pathologies have been the basis of study over the past decades. Herein, we recapitulate these findings in order to highlight the best underlying mechanisms found to date. We also seek to elucidate how miRNA dysregulation can be associated with many cardiovascular diseases. Furthermore, we discuss miR regulation mechanism during in early development in vivo and invitro. Since many of the miR’s are precursors to transcriptional regulation, we relate back to their molecular control as we can then look together at the fundamental disease they might be exacerbating by this dysregulation.
Frontiers in Cardiovascular Medicine, 2022
Human heart development is a complex and tightly regulated process, conserving proliferation, and multipotency of embryonic cardiovascular progenitors. At terminal stage, progenitor cell type gets suppressed for terminal differentiation and maturation. In the human heart, most cardiomyocytes are terminally differentiated and so have limited proliferation capacity. MicroRNAs (miRNAs) are non-coding single-stranded RNA that regulate gene expression and mRNA silencing at the post-transcriptional level. These miRNAs play a crucial role in numerous biological events, including cardiac development, and cardiomyocyte proliferation. Several cardiac cells specific miRNAs have been discovered. Inhibition or overexpression of these miRNAs could induce cardiac regeneration, cardiac stem cell proliferation and cardiomyocyte proliferation. Clinical application of miRNAs extends to heart failure, wherein the cell cycle arrest of terminally differentiated cardiac cells inhibits the heart regenerati...
Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2
Cell, 2007
MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cellcycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 ''seed matches'' and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian lossof-function models in revealing physiologic miRNA targets.
Complexity of Murine Cardiomyocyte miRNA Biogenesis, Sequence Variant Expression and Function
PLoS ONE, 2012
microRNAs (miRNAs) are critical to heart development and disease. Emerging research indicates that regulated precursor processing can give rise to an unexpected diversity of miRNA variants. We subjected small RNA from murine HL-1 cardiomyocyte cells to next generation sequencing to investigate the relevance of such diversity to cardiac biology. ,40 million tags were mapped to known miRNA hairpin sequences as deposited in miRBase version 16, calling 403 generic miRNAs as appreciably expressed. Hairpin arm bias broadly agreed with miRBase annotation, although 44 miR* were unexpectedly abundant (.20% of tags); conversely, 33 -5p/-3p annotated hairpins were asymmetrically expressed. Overall, variability was infrequent at the 59 start but common at the 39 end of miRNAs (5.2% and 52.3% of tags, respectively). Nevertheless, 105 miRNAs showed marked 59 isomiR expression (.20% of tags). Among these was miR-133a, a miRNA with important cardiac functions, and we demonstrated differential mRNA targeting by two of its prevalent 59 isomiRs. Analyses of miRNA termini and base-pairing patterns around Drosha and Dicer cleavage regions confirmed the known bias towards uridine at the 59 most position of miRNAs, as well as supporting the thermodynamic asymmetry rule for miRNA strand selection and a role for local structural distortions in fine tuning miRNA processing. We further recorded appreciable expression of 5 novel miR*, 38 extreme variants and 8 antisense miRNAs. Analysis of genome-mapped tags revealed 147 novel candidate miRNAs. In summary, we revealed pronounced sequence diversity among cardiomyocyte miRNAs, knowledge of which will underpin future research into the mechanisms involved in miRNA biogenesis and, importantly, cardiac function, disease and therapy. Citation: Humphreys DT, Hynes CJ, Patel HR, Wei GH, Cannon L, et al. (2012) Complexity of Murine Cardiomyocyte miRNA Biogenesis, Sequence Variant Expression and Function. PLoS ONE 7(2): e30933.
The Journal of physiology, 2018
Myocardial infarction is a primary contributor towards the global burden of cardiovascular disease. Rather than repairing the existing damage of myocardial infarction, current treatments only address the symptoms of the disease and reducing the risk of a secondary infarction. Cardiac regenerative capacity is dependent on cardiomyocyte proliferation, which concludes soon after birth in humans and precocial species such as sheep. Human fetal cardiac tissue has some ability to repair following tissue damage, whereas a fully matured human heart has minimal capacity for cellular regeneration. This is in contrast to neonatal mice and adult zebrafish hearts, which retain the ability to undergo cardiomyocyte proliferation and can regenerate cardiac tissue after birth. In mice and zebrafish models, microRNAs (miRNAs) have been implicated in the regulation of genes involved in cardiac cell cycle progression and regeneration. However, the significance of miRNA regulation in cardiomyocyte proli...