Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

Timofeyev, Valeriy; Li, Ning; Kim, Catherine; Ledford, Hannah A.; Sirish, Padmini; Lau, Victor C.; Fayyaz, Kiran; Singapuri, Anil; López, Javier E.; Knowlton, Anne A; Zhang, Xiao Dong; Chiamvimonvat, Nipavan

doi:10.1161/circep.114.002162

Cited by 19 publications

(16 citation statements)

References 53 publications

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“…In our previous study we showed that cardiomyocyte-specific inactivation of the cAMP-dependent transcriptional activator CREB leads to AP prolongation due to an I to reduction likewise along a decrease of Kcnd2 mRNA and Kv4.2 protein in VCMs [ 34 ]. Our own results are supported by a recent study that postulates ICER as a repressor of Kcnd2 /KV4.2/ I to by repressing miR-1 [ 28 ]. Hence, data from three independent mouse models strongly suggest that inactivation or repression of cAMP-dependent transcription leads to I to remodeling.…”

Section: Discussionsupporting

confidence: 86%

Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes

et al. 2016

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Chronic β-adrenergic stimulation is regarded as a pivotal step in the progression of heart failure which is associated with a high risk for arrhythmia. The cAMP-dependent transcription factors cAMP-responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) mediate transcriptional regulation in response to β-adrenergic stimulation and CREM repressor isoforms are induced after stimulation of the β-adrenoceptor. Here, we investigate whether CREM repressors contribute to the arrhythmogenic remodeling in the heart by analyzing arrhythmogenic alterations in ventricular cardiomyocytes (VCMs) from mice with transgenic expression of the CREM repressor isoform CREM-IbΔC-X (TG). Patch clamp analyses, calcium imaging, immunoblotting and real-time quantitative RT-PCR were conducted to study proarrhythmic alterations in TG VCMs vs. wild-type controls. The percentage of VCMs displaying spontaneous supra-threshold transient-like Ca2+ releases was increased in TG accompanied by an enhanced transduction rate of sub-threshold Ca2+ waves into these supra-threshold events. As a likely cause we discovered enhanced NCX-mediated Ca2+ transport and NCX1 protein level in TG. An increase in INCX and decrease in Ito and its accessory channel subunit KChIP2 was associated with action potential prolongation and an increased proportion of TG VCMs showing early afterdepolarizations. Finally, ventricular extrasystoles were augmented in TG mice underlining the in vivo relevance of our findings. Transgenic expression of CREM-IbΔC-X in mouse VCMs leads to distinct arrhythmogenic alterations. Since CREM repressors are inducible by chronic β-adrenergic stimulation our results suggest that the inhibition of CRE-dependent transcription contributes to the formation of an arrhythmogenic substrate in chronic heart disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-016-0532-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes

et al. 2016

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“…Enhanced expression of the cAMP early repressor suppressed the expression of miR-1 and miR-133a, leading to hypertrophy and electrical remodeling, respectively. Meanwhile, by delivering miR-1 and miR-133a in vivo , inducible cAMP early repressor expression was blocked so that both hypertrophy and electrical remodeling were alleviated (Myers et al, 2015 ). Therefore, feedback mechanisms for cardiac-specific miR133a, miR-1, and cAMP signaling pathways exist in cardiac hypertrophy and electrical remodeling, providing proof-of-concept for the potential applications of miR-1 and miR-133a therapy for MI.…”

Section: The Roles Of Mir-133 In Cardiac Remodelingmentioning

confidence: 99%

“…Hyperpolarization-activated non-specific cation channels (HCNs) conduct a mixed K + /Na + depolarizing current, which is activated by cAMP and hyperpolarization. Once the HCNs are activated in the myocardial diastolic period, membrane depolarization is triggered immediately (Myers et al, 2015 ; Wen and Li, 2017 ). In the right atrial appendage from patients with AF, the levels of HCN2 and HCN4 channels are significantly increased, accompanied by a decrease in miR-133 and miR-1 levels with aging.…”

Section: The Roles Of Mir-133 In Cardiac Remodelingmentioning

confidence: 99%

miR-133: A Suppressor of Cardiac Remodeling?

Zhou

2018

Front. Pharmacol.

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114

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Cardiac remodeling, which is characterized by mechanical and electrical remodeling, is a significant pathophysiological process involved in almost all forms of heart diseases. MicroRNAs (miRNAs) are a group of non-coding RNAs of 20–25 nucleotides in length that primarily regulate gene expression by promoting mRNA degradation or post-transcriptional repression in a sequence-specific manner. Three miR-133 genes have been identified in the human genome, miR-133a-1, miR-133a-2, and miR-133b, which are located on chromosomes 18, 20, and 6, respectively. These miRNAs are mainly expressed in muscle tissues and appear to repress the expression of non-muscle genes. Based on accumulating evidence, miR-133 participates in the proliferation, differentiation, survival, hypertrophic growth, and electrical conduction of cardiac cells, which are essential for cardiac fibrosis, cardiac hypertrophy, and arrhythmia. Nevertheless, the roles of miR-133 in cardiac remodeling are ambiguous, and the mechanisms are also sophisticated, involving many target genes and signaling pathways, such as RhoA, MAPK, TGFβ/Smad, and PI3K/Akt. Therefore, in this review, we summarize the critical roles of miR-133 and its potential mechanisms in cardiac remodeling.

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“…Recent technical developments in 'omics' technologies promise to be at the forefront of this field. At the gene level, next generation gene sequencing technologies have led to the identification of microRNAs and long non-coding RNAs (lncRNAs) that play critical roles in regulating transcription and translation of many genes, including ion channel genes (Greco & Condorelli, 2015;Myers et al 2015). At the protein level, new mass spectrometry methods have enabled global analyses of integrated responses rather than the analysis of individual components (Ferreira et al 2015).…”

Section: Mechanisms Of Cardiac Electrical Remodelling In Acquired Dismentioning

confidence: 99%

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

Chiamvimonvat

Chen‐Izu

Clancy

et al. 2017

The Journal of Physiology

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This is the second of the two White Papers from the fourth UC Davis Cardiovascular Symposium Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias (3-4 March 2016), a biennial event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was 'K channels and regulation', and the objectives of the conference were severalfold: (1) to identify current knowledge gaps; (2) to understand what may go wrong in the diseased heart and why; (3) to identify possible novel therapeutic targets; and (4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias. The sessions of the Symposium focusing on the functional roles of the cardiac K channel in health and disease, as well as K channels as therapeutic targets, were contributed by Ye Chen-Izu, Gideon Koren, James Weiss, David Paterson, David Christini, Dobromir Dobrev, Jordi Heijman, Thomas O'Hara, Crystal Ripplinger, Zhilin Qu, Jamie Vandenberg, Colleen Clancy, Isabelle Deschenes, Leighton Izu, Tamas Banyasz, Andras Varro, Heike Wulff, Eleonora Grandi, Michael Sanguinetti, Donald Bers, Jeanne Nerbonne and Nipavan Chiamvimonvat as speakers and panel discussants. This article summarizes state-of-the-art knowledge and controversies on the functional roles of cardiac K channels in normal and diseased heart. We endeavour to integrate current knowledge at multiple scales, from the single cell to the whole organ levels, and from both experimental and computational studies.

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Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

Cited by 19 publications

References 53 publications

Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes

Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes

miR-133: A Suppressor of Cardiac Remodeling?

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

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