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1.
Mol Ther ; 28(6): 1506-1517, 2020 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-32304667

RESUMEN

Circular RNAs (circRNAs) sequester microRNAs (miRNAs) and repress their endogenous activity. We hypothesized that artificial circRNA sponges (circmiRs) can be constructed to target miRNAs therapeutically, with a low dosage requirement and extended half-lives compared to current alternatives. This could present a new treatment approach for critical global pathologies, including cardiovascular disease. Here, we constructed a circmiR sponge to target known cardiac pro-hypertrophic miR-132 and -212. Expressed circmiRs competitively inhibited miR-132 and -212 activity in luciferase rescue assays and showed greater stability than linear sponges. A design containing 12 bulged binding sites with 12 nucleotides spacing was determined to be optimal. Adeno-associated viruses (AAVs) were used to deliver circmiRs to cardiomyocytes in vivo in a transverse aortic constriction (TAC) mouse model of cardiac disease. Hypertrophic disease characteristics were attenuated, and cardiac function was preserved in treated mice, demonstrating the potential of circmiRs as novel therapeutic tools. Subsequently, group I permutated intron-exon sequences were used to directly synthesize exogenous circmiRs, which showed greater in vitro efficacy than the current gold standard antagomiRs in inhibiting miRNA function. Engineered circRNAs thus offer exciting potential as future therapeutics.


Asunto(s)
Cardiomegalia/fisiopatología , Regulación de la Expresión Génica , MicroARNs/genética , Interferencia de ARN , ARN Circular/genética , Animales , Secuencia de Bases , Sitios de Unión , Cardiomegalia/diagnóstico , Cardiomegalia/etiología , Cardiomegalia/terapia , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Ingeniería Genética , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Pruebas de Función Cardíaca , Ratones , MicroARNs/administración & dosificación , MicroARNs/química , Estabilidad del ARN , ARN Circular/administración & dosificación , ARN Circular/química
2.
Genes (Basel) ; 12(3)2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803261

RESUMEN

Congenital heart disease (CHD) is the most common birth defect among newborns worldwide and contributes to significant infant morbidity and mortality. Owing to major advances in medical and surgical management, as well as improved prenatal diagnosis, the outcomes for these children with CHD have improved tremendously so much so that there are now more adults living with CHD than children. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. For this reason, the complex process of cardiogenesis, which is governed by multiple interlinked and dose-dependent pathways, is a well investigated process. In addition to the sequence of the genome, the contribution of epigenetics to cardiogenesis is increasingly recognized. Significant progress has been made dissecting the epigenome of the heart and identified associations with cardiovascular diseases. The role of epigenetic regulation in cardiac development/cardiogenesis, using tissue and animal models, has been well reviewed. Here, we curate the current literature based on studies in humans, which have revealed associated and/or causative epigenetic factors implicated in CHD. We sought to summarize the current knowledge on the functional role of epigenetics in cardiogenesis as well as in distinct CHDs, with an aim to provide scientists and clinicians an overview of the abnormal cardiogenic pathways affected by epigenetic mechanisms, for a better understanding of their impact on the developing fetal heart, particularly for readers interested in CHD research.


Asunto(s)
Epigénesis Genética/genética , Cardiopatías Congénitas/genética , Animales , Genoma/genética , Corazón/fisiología , Humanos , Transducción de Señal/genética
3.
Cardiovasc Res ; 116(2): 269-278, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31552406

RESUMEN

The combination of next-generation sequencing, advanced bioinformatics analysis, and molecular research has now established circular RNAs (circRNAs) as a heterogeneous group of non-coding RNA that is widely and abundantly expressed. CircRNAs are single-stranded RNA, covalently backspliced to form closed circular loops. Different models of back-splicing have been proposed, and mechanisms for circRNA function include sequestering microRNAs, direct interaction with proteins, regulation of transcription, and translation. Exploring the role of circRNAs in different disease settings, and understanding how they contribute to disease progression promises to provide valuable insight into potential novel therapeutic approaches. Here, we review the growing number of published research on circRNAs in the heart and cardiovascular system and summarize the circRNAs that have been implicated in disease.


Asunto(s)
Vasos Sanguíneos/metabolismo , Enfermedades Cardiovasculares/metabolismo , Corazón , Miocardio/metabolismo , ARN Circular/metabolismo , Animales , Vasos Sanguíneos/patología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Regulación de la Expresión Génica , Humanos , Miocardio/patología , ARN Circular/biosíntesis , ARN Circular/genética , Transducción de Señal
4.
Cardiovasc Res ; 115(14): 1998-2007, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31114845

RESUMEN

AIMS: We and others have previously described the expression landscape of circular RNA (circRNA) in mouse and human hearts. However, the functional relevance of many of these abundantly expressed cardiomyocyte circRNA remains to be fully explored. Among the most abundant circRNA, one stems from the sodium-calcium exchanger gene, Slc8a1, exon 2 locus. Because of its very high abundance in cardiomyocytes we investigated the possible role of circSlc8a1 in the heart. METHODS AND RESULTS: We performed a miRNA screen using an array of 752 miRNAs with RNA recovered from a pull-down of endogenous cardiomyocyte circSlc8a1. MicroRNA-133a (miR-133a), with a prior well-recognized role in cardiac hypertrophy, was highly enriched in the fraction of circSlc8a1 pull-down (adjusted P-value < 0.001). We, therefore, followed-up validation of the functional interaction between circSlc8a1 and miR-133 using luciferase assays and reciprocal pull-down assays. In vivo, AAV9-mediated RNAi knockdown of circSlc8a1 attenuates cardiac hypertrophy from pressure-overload, whereas forced cardiomyocyte specific overexpression of circSlc8a1 resulted in heart failure. Molecular analyses showed targets of miR-133a including serum response factor (Srf), connective tissue growth factor (Ctgf), adrenoceptor beta 1 (Adrb1), and adenylate cyclase 6 (Adcy6) to be regulated by circSlc8a1-directed intervention of knockdown and overexpression. CONCLUSION: In summary, circSlc8a1 can function as an endogenous sponge for miR-133a in cardiomyocytes. We propose that circSlc8a1 may serve as a novel therapeutic target for cardiac hypertrophy.


Asunto(s)
Cardiomegalia/metabolismo , Insuficiencia Cardíaca/metabolismo , MicroARNs/metabolismo , Miocitos Cardíacos/metabolismo , ARN Circular/metabolismo , Intercambiador de Sodio-Calcio/genética , Adenilil Ciclasas/genética , Adenilil Ciclasas/metabolismo , Animales , Cardiomegalia/genética , Cardiomegalia/fisiopatología , Cardiomegalia/prevención & control , Células Cultivadas , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Exones , Regulación de la Expresión Génica , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Ratones , MicroARNs/genética , ARN Circular/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Factor de Respuesta Sérica/genética , Factor de Respuesta Sérica/metabolismo , Transducción de Señal , Volumen Sistólico , Función Ventricular Izquierda , Remodelación Ventricular
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