Chronic atrial fibrillation up-regulates β1-Adrenoceptors affecting repolarizing currents and action potential duration

Fuente, Marta González de la; Barana, Adriana; Gómez, Ricardo; Amorós, Irene; Dolz-Gaitón, Pablo; Sacristán, Silvia; Atienza, Felipe; Pita, Ana; Pinto, Ángel González; Fernández-Avilés, Francisco; Caballero, Ricardo; Tamargo, Juan; Delpón, Eva

doi:10.1093/cvr/cvs313

Cited by 44 publications

(57 citation statements)

References 26 publications

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“…Reduction of I Ca,L density by CAF has been consistently described in patients, 2,3,6,7,16 as well as in AF experimental models, 4 and it has been proposed to be triggered by Ca 2+ overload secondary to the rapid atrial rates. 29 The molecular mechanisms underlying I Ca,L downregulation are complex and can include impaired Cav1.2 protein trafficking induced by a zinc-binding protein, activation of the Ca 2+ /calmodulin/calcineurin/nuclear factor of activated T cells system causing transcriptional downregulation of the Cav1.2 α-subunit, Ca 2+ channel dephosphorylation because of serine/threonine protein phosphatase activation, enhanced Cav1.2 α-subunit S-nitrosylation, activation of calpains, ankyrin-B dysfunction, or impaired src kinase activity.…”

Section: Mir-21 Regulates Calcium Channel Subunits Expression and Decmentioning

confidence: 88%

“…5,16 From each sample, 2 RNA fractions were obtained: a large RNA (>200 nucleotides) fraction and a separate miRNA-enriched fraction. Quantitative polymerase chain reaction (qPCR) was performed using TaqMan gene and miRNA expression assays (Life Technologies, USA).…”

Section: Real-time Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

“…5,16 Series resistance was compensated manually and usually ≥80% compensation was achieved. Under our experimental conditions, no significant voltage errors (<5 mV) caused by series resistance were expected with the micropipettes used.…”

Section: Calcium Current Recordingsmentioning

confidence: 99%

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Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current

Barana

Matamoros

Dolz-Gaitón

et al. 2014

Circ: Arrhythmia and Electrophysiology

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Background— Atrial fibrillation is characterized by progressive atrial structural and electrical changes (atrial remodeling) that favor arrhythmia recurrence and maintenance. Reduction of L-type Ca 2+ current ( I Ca,L ) density is a hallmark of the electrical remodeling. Alterations in atrial microRNAs could contribute to the protein changes underlying atrial fibrillation–induced atrial electrical remodeling. This study was undertaken to compare miR-21 levels in isolated myocytes from atrial appendages obtained from patients in sinus rhythm and with chronic atrial fibrillation (CAF) and to determine whether L-type Ca 2+ channel subunits are targets for miR-21. Methods and Results— Quantitative polymerase chain reaction analysis showed that miR-21 was expressed in human atrial myocytes from patients in sinus rhythm and that its expression was significantly greater in CAF myocytes. There was an inverse correlation between miR-21 and the mRNA of the α1c subunit of the calcium channel (CACNA1C) expression and I Ca,L density. Computational analyses predicted that CACNA1C and the mRNA of the β2 subunit of the calcium channel (CACNB2) could be potential targets for miR-21. Luciferase reporter assays demonstrated that miR-21 produced a concentration-dependent decrease in the luciferase activity in Chinese Hamster Ovary cells transfected with CACNA1C and CACNB2 3′ untranslated region regions. miR-21 transfection in HL-1 cells produced changes in I Ca,L properties qualitatively similar to those produced by CAF (ie, a marked reduction of I Ca,L density and shift of the inactivation curves to more depolarized potentials). Conclusions— Our results demonstrated that CAF increases miR-21 expression in enzymatically isolated human atrial myocytes. Moreover, it decreases I Ca,L density by downregulating Ca 2+ channel subunits expression. These results suggested that this microRNA could participate in the CAF-induced I Ca,L downregulation and in the action potential duration shortening that maintains the arrhythmia.

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Section: Mir-21 Regulates Calcium Channel Subunits Expression and Decmentioning

confidence: 88%

Section: Real-time Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

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Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current

Barana

Matamoros

Dolz-Gaitón

et al. 2014

Circ: Arrhythmia and Electrophysiology

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“…136 There is evidence for increased I Ks in patients with cAF, which might contribute to APD shortening. 137,138 The molecular mechanisms underlying increased I Ks are unknown. Increased, decreased, and unaltered mRNA levels of the underlying KCNQ1 α-subunit have been reported in patients with cAF.…”

Section: Apd Shorteningmentioning

confidence: 99%

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Heijman

Voigt

Nattel

et al. 2014

Circulation Research

551

603

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Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca 2+ -handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management.

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“…141). Furthermore, a recent study on chronic AF in humans showed a chamberspecific upregulation of ␤1 adrenergic receptors, which led to dramatic effects on several repolarizing currents, foremost I Ks (150).…”

Section: Posttranslational Regulation Of Potassium Channels In Proteimentioning

confidence: 99%

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

191

197

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About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.

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Chronic atrial fibrillation up-regulates β1-Adrenoceptors affecting repolarizing currents and action potential duration

Cited by 44 publications

References 26 publications

Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current

Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

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