miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation

Cañón, Susana; Caballero, Ricardo; Herraiz‐Martínez, Adela; Pérez-Hernández, Marta; López, Begoña; Atienza, Felipe; Jalife, José; Hove‐Madsen, Leif; Delpón, Eva; Bernad, António

doi:10.1016/j.yjmcc.2016.08.012

Cited by 62 publications

(49 citation statements)

References 40 publications

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“…Although an impact of miRNAs on cardiac excitation generation and propagation is widely accepted [29,33], the knowledge is still incomplete. In the present study, we provide evidence for a role of the clustered miR-221 and miR-222 in cardiac electrophysiology with potential pathophysiological relevance.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that miRs might be involved in the regulation of this ion channel. It has been suggested that besides miR-221 and -222, also miR-208b [29], miR-29a-3p [51], and miR-21 [52] bind to the 3′-UTR of Cacna1c, and thereby reduce I Ca,L . From these miRs, only miR-208b was altered in EGFR Δ/ΔVSMC&CM mice.…”

Section: Discussionmentioning

confidence: 99%

“…As the impact of mmu-miR-208b-3p on structural and electrical heart remodeling [29] and as a marker for an increased risk for death after myocardial infarction [30] has already been reported, we focused on miR-221/222, the second and third most upregulated miR. The changes in miR content were validated via TaqMan qRT-PCR ( Fig.…”

Section: Validation Of Differential Microrna Expressionmentioning

confidence: 99%

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miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

Binas

Knyrim

Hupfeld

et al. 2019

Cell. Mol. Life Sci.

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MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among others cardiac hypertrophy and atrial fibrillation. The aim of our study was to evaluate the impact of miR-221/222 on cardiac electrical remodeling. Cardiac miR expression was analyzed in a mouse model with altered electrocardiography parameters and severe heart hypertrophy. Next generation sequencing revealed 14 differentially expressed miRs in hypertrophic hearts, with miR-221 and-222 being the strongest regulated miR-cluster. This increase was restricted to cardiomyocytes and not observed in cardiac fibroblasts. Additionally, we evaluated the change of miR-221/222 in vivo in two models of pharmacologically induced heart hypertrophy (angiotensin II, isoprenaline), thereby demonstrating a stimulus-induced increase in miR-221/222 in vivo by angiotensin II but not by isoprenaline. Whole transcriptome analysis by RNA-seq and qRT-PCR validation revealed an enriched number of downregulated mRNAs coding for proteins located in the T-tubule, which are also predicted targets for miR-221/222. Among those, mRNAs were the L-type Ca 2+ channel subunits as well as potassium channel subunits. We confirmed that both miRs target the 3′-untranslated regions of Cacna1c and Kcnj5. Furthermore, enhanced expression of these miRs reduced L-type Ca 2+ channel and Kcnj5 channel abundance and function, which was analyzed by whole-cell patch clamp recordings or Western blot and flux measurements, respectively. miR-221 and-222 contribute to the regulation of L-type Ca 2+ channels as well as Kcnj5 channels and, therefore, potentially contribute to disturbed cardiac excitation generation and propagation. Future studies will have to evaluate the pathophysiological and clinical relevance of aberrant miR-221/222 expression for electrical remodeling. Keywords Electrical remodeling • Cardiomyocytes • Angiotensin II • Heart hypertrophy Abbreviations ANOVA Analysis of variance AUC Area under the curve AII Angiotensin II Bp Base pair BW Body weight Cacna1C Calcium voltage-gated channel subunit α1 C, L-type Cacnb2 Calcium voltage-gated channel auxiliary subunit β2 Cacna2d1 Voltage-dependent calcium channel subunit α2/δ1 Cav1.2 L-type Ca 2+ channel CCH Carbachol, acetylcholine analog cDNA Complementary DNA CE Carbachol effect CM Cardiomyocyte ddPCR Droplet digital PCR Cellular and Molecular Life Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Validation Of Differential Microrna Expressionmentioning

confidence: 99%

See 1 more Smart Citation

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

Binas

Knyrim

Hupfeld

et al. 2019

Cell. Mol. Life Sci.

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“…23) The miR-208 family was proved to control myosin content and muscle performance and involved in maintaining functionality and survival of cardiac muscle cells. 24,25) Recently, researches have verified that miR-208a could sufficiently induce arrhythmias and cardiac remodeling and regulate the component expression in hypertrophy pathway, as well as the cardiac conduction system. 26) In the present study, miR-208a was proved to be upregulated in H9c2 cells after the simulated I/R injury, and miR-208a also exhibited the effect of promoting on cell injury, suggesting that miR-208a, as a cardiacenriched miRNA, was also involved in I/R injury.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-208a Regulates H9c2 Cells Simulated Ischemia-Reperfusion Myocardial Injury via Targeting CHD9 through Notch/NF-kappa B Signal Pathways

Zhang

et al. 2018

Int. Heart J.

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Ischemic reperfusion (I/R) injury is a serious problem in the treatment of ischemic heart disease. MicroRNA-208a (miR-208a) is a cardiac-specific or cardiac-enriched miRNA. This study was aimed to assess the role of miR-208a in I/R injury. H9c2 cells were used to simulate I/R injury in vitro. miR-208a expression level was measured by qPCR. H9c2 cells after simulated I/R injury were transfected with miR-208a mimic, AOS-miR-208a or negative controls. LDH release, MDA and SOD contents were measured by corresponding purchased detection kits, respectively. Cell apoptosis were measured by flow cytometry. Then binding effect of miR-208a on CHD9 3'UTR was detected by Dual-Luciferase activity assay. After miRNA or CHD9 overexpression transfections, expressions of apoptosis-related factors, CHD9, Notch 1, IκBα, and p65 in H9c2 cells after I/R injury were measured by Western blot assay. Results showed that in H9c2 cells after simulated I/R injury, miR-208a was upregulated. The elevated miR-208a expression enhanced the injury of cells and promoted cell apoptosis. miR-208a directly target 3'UTR of CHD9 and negatively regulated CHD9 expression. Overexpression of CHD9 rescued I/R injury that was enhanced by miR-208a mimic transfection. miR-208a was positively related with activation of Notch/NF-B signal pathways via CHD9. In conclusion, miR-208a was a cardiac-enriched miRNA and CHD9 is a direct target of miR-208a, which was also related with Notch/NFB signal pathway during I/R injury. miR-208a has potential to be a biomarker for early diagnosis of I/R injury and might be used as a treatment target in clinical treatment of ischemic heart disease.

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“…For instance, miR-208b was demonstrated to be upregulated in patients with AF and an ovine model. Furthermore, a high miR-208b level was demonstrated to increase MYH7 expression and alter the subcellular localization of connexin43 (39). miR-208b has been reported to reduce the expression levels of CaV1.2 and SERCA2, which further reduce L-type Ca 2+ current density and sarcoplasmic reticulum Ca 2+ load/release, respectively (39).…”

Section: Discussionmentioning

confidence: 99%

Characterization of circRNA‑associated ceRNA networks in patients with nonvalvular persistent atrial fibrillation

Zhang

Liu

et al. 2018

Mol Med Report

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Circular RNAs (circRNAs) are non-coding RNAs forming closed-loop structures, and their aberrant expression may lead to disease. However, the potential network of circRNA-associated competing endogenous RNA (ceRNA) involved in nonvalvular persistent atrial fibrillation (NPAF) has not been previously reported. In the present study, four left atrial appendages (LAA) of patients with NPAF and four normal LAAs were examined via RNA sequencing, and their potential functions were investigated via bioinformatics analysis. The circRNA-enriched genes were analyzed using Gene Ontology (GO) categories, while the enrichment of circRNAs was detected via the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A total of 296 significantly dysregulated circRNA transcripts were obtained, with 238 upregulated and 58 downregulated. A number of circRNAs were further confirmed using reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the more comprehensive circRNA-associated ceRNA networks were examined in patients with NPAF. GO categories and KEGG annotation analysis of circRNAs revealed that the circRNA-associated ceRNA networks were likely to influence AF though alterations in calcium and cardiac muscle contraction. The circRNA-associated ceRNA networks revealed that dysregulated circRNAs in NPAF may be involved in regulating hsa-microRNA (miR)-208b and hsa-miR-21. To the best of our knowledge, this study presents the circRNA-associated ceRNA networks in NPAF for the first time, which may have potential implications for the pathogenesis of AF. This study reveals a potential perspective from which to investigate circRNAs in circRNA-associated ceRNA networks (hsa_circRNA002085, hsa_circRNA001321) in NPAF, and provides a potential biomarker for AF. AF causes 130,000 mortalities/year in the USA (5) and affects 2-3% of the European population (4,6,7). The number of patients with AF is predicted to increase rapidly in the coming decades and to gradually reduce quality of life (8,9). In Asia, the number of patients with AF and AF-associated stroke is estimated to reach 72 million and 2.9 million by 2050, respectively (3,10). Warfarin is commonly applied to treat nonvalvular persistent atrial fibrillation (NPAF) and research on NPAF has been extensive (11,12), although the current treatment options remain inadequate. Thus, it is necessary to identify a novel biomarker for the prediction, diagnosis and treatment of NPAF. Circular RNAs (circRNAs), non-coding RNAs identified in 1991 (13), regulate gene expression and act as microRNA (miRNA) 'sponges' by competing with endogenous RNA (ceRNA) networks to suppress specific miRNA activity (14,15). circRNAs are associated with numerous diseases and may serve an important role in diagnosis or pathogenesis (16,17). Previous

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miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation

Cited by 62 publications

References 40 publications

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density

MicroRNA-208a Regulates H9c2 Cells Simulated Ischemia-Reperfusion Myocardial Injury via Targeting CHD9 through Notch/NF-kappa B Signal Pathways

Characterization of circRNA‑associated ceRNA networks in patients with nonvalvular persistent atrial fibrillation

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