Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,Land Itoin rapid atrial pacing in rabbits

Bosch, Ralph F.; Scherer, Constanze R; Rüb, Norman; Wöhrl, Stefan; Steinmeyer, Klaus; Haase, Hannelore; Büsch, Andreas; Seipel, L; Kühlkamp, Volker

doi:10.1016/s0735-1097(02)02922-4

Cited by 105 publications

(68 citation statements)

References 32 publications

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“…Rapid atrial activation causes Ca 2+ loading, which activates the Ca 2+ /calmodulin/calcineurin/NFAT system, causing transcriptional downregulation of the Cav1.2 α-subunit (72,73). Other potential contributors include downregulation of accessory β 1 -, β 2a -, β 2b -, β 3 -, and α 2 δ 2 -subunits (19,66,74,75), Ca 2+ channel dephosphorylation due to type 1 (PP1) and type 2A (PP2A) serine/threonine protein phosphatase activation (28,66), and enhanced Cav1.2 α-subunit S-nitrosylation (76). MicroRNAs (miRNAs) appear to play a major role in AF (77).…”

Section: Molecular Mechanisms Underlying Functional Substrates For Afmentioning

confidence: 99%

Recent advances in the molecular pathophysiology of atrial fibrillation

Wakili¹,

Voigt²,

Kääb³

et al. 2011

J. Clin. Invest.

483

461

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Atrial fibrillation (AF) is an extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality. The mechanisms underlying AF are complex, involving both increased spontaneous ectopic firing of atrial cells and impulse reentry through atrial tissue. Over the past ten years, there has been enormous progress in understanding the underlying molecular pathobiology. This article reviews the basic mechanisms and molecular processes causing AF. We discuss the ways in which cardiac disease states, extracardiac factors, and abnormal genetic control lead to the arrhythmia. We conclude with a discussion of the potential therapeutic implications that might arise from an improved mechanistic understanding.Authorship note: Reza Wakili and Niels Voigt contributed equally to this work.

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Section: Molecular Mechanisms Underlying Functional Substrates For Afmentioning

confidence: 99%

Recent advances in the molecular pathophysiology of atrial fibrillation

Wakili¹,

Voigt²,

Kääb³

et al. 2011

J. Clin. Invest.

483

461

View full text Add to dashboard Cite

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“…Some investigations revealed decreased expression of Cav1.2 [67,68], α2/δ1 [69], β1(b) [69] and α1d [68], whereas other studies showed unchanged Cav1.2 [70], β1(a,c) [69] or β2a subunit expression of I Ca,L [57,66]. Several factors might explain these discrepancies, including species differences and time-dependent changes in remodeling in animal models.…”

Section: Downregulation Of L-type Ca 2+ Channelmentioning

confidence: 99%

Role of abnormal sarcoplasmic reticulum function in atrial fibrillation

Wehrens¹,

Ather²,

Dobrev³

2010

Therapy

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SummaryAtrial fibrillation (AF) is the most common cardiac arrhythmia, and is a cause of significant morbidity and mortality if left untreated. AF has been associated with profound changes in sarcoplasmic reticulum Ca 2+ homeostasis, which might contribute to both reduced contractile function and increased arrhythmogenesis in atria. Studies in human tissue samples and various animal models of AF have revealed changes in both expression levels and posttranslational modifications of key Ca 2+ handling proteins, which may contribute to arrhythmogenesis. In this review, we will focus on the molecular basis of alterations in sarcoplasmic reticulum Ca 2+ handling in AF and their potential therapeutic implications.

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“…1 Interestingly, our data showed that β2 mRNA was decreased, but β3 mRNA was increased, in hypertrophied RA cells, in contrast to a previous study in which the levels of mRNA expression for both the β2 and β3 subunits were equally decreased in a rapid atrial pacing animal model. 4 The function of auxiliary β subunits of the L-type Ca 2+ channel is not only to promote the membrane expression of CaV1.2 subunits, but also to regulate inactivation kinetics. 15,18 Therefore, it is likely that alternation of the β2 and β3 subunits influences the inactivation kinetics in hypertrophied RA cells.…”

Section: Ical Remodeling In Mct-treated Rat Atriamentioning

confidence: 99%

“…2,3 Recent studies demonstrated that the densities of the L-type calcium (Ca 2+ ) current (ICaL), transient outward current (Ito), and voltage-dependent Na + current (INa) are decreased in experimental animal models of atrial tachycardia-related AF. [4][5][6] In contrast to tachycardia-induced ionic remodeling, several clinical and experimental studies have indicated a decrease, no change, or even an increase in the ICaL density in chronic heart failure (CHF), 1,7,8 depending on the experimental conditions. Nonetheless, it is generally agreed that a possible change in ICaL is a key factor in electrical remodeling of cardiac myocytes in CHF and/or hypertrophy.…”

mentioning

confidence: 99%

Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

Koyama

Ono

Watanabe

et al. 2009

Circ J

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t is well known that fibrillating or hemodynamically overloaded atria are subject to cellular electrical remodeling, which is characterized by shortening of the action potential 1 and often contributes to the occurrence and persistence of atrial fibrillation (AF). AF and chronic obstructive pulmonary disease (COPD) frequently coexist and complicate treatment of both clinical conditions. 2,3 COPD patients are susceptible to secondary pulmonary hypertension (PH), and the resulting hemodynamic changes, and in addition hypoxia, hypercapnia, acid-base disorders, disturbed sympathovagal balance, and medication can lead to the development of AF. 2,3 Recent studies demonstrated that the densities of the L-type calcium (Ca 2+ ) current (ICaL), transient outward current (Ito), and voltage-dependent Na + current (INa) are decreased in experimental animal models of atrial tachycardia-related AF. [4][5][6] In contrast to tachycardia-induced ionic remodeling, several clinical and experimental studies have indicated a decrease, no change, or even an increase in the ICaL density in chronic heart failure (CHF), 1,7,8 depending on the experimental conditions. Nonetheless, it is generally agreed that a possible change in ICaL is a key factor in electrical remodeling of cardiac myocytes in CHF and/or hypertrophy. In addition, the T-type Ca 2+ channel is involved in electrical remodeling during CHF or hypertrophy. The T-type Ca 2+ channel is normally expressed in embryonic and neonatal myocytes, and in the conducting system of the adult heart, 9 and in rats it is re-expressed in pathologic conditions such as ventricular hypertrophy and post-myocardial infarction. 10 In the present study, the electrical properties of ICaL and ICaT were characterized in rat right atrial cells with monocrotaline (MCT)-induced PH, and the possible causes are discussed in relation to changes in the expression and function of Ca 2+ channel subunits. Methods AnimalsThe Animal Ethics Committee of Akita University School of Medicine, Japan, approved the study protocol. Four-week-old Wistar rats (CLEA Japan, Tokyo, Japan), weighing 140-150 g each, were treated with 500 mg MCT (Crotaline; Sigma, St Louis, MO, USA) to produce PH. A single dose of MCT 60 mg/kg was injected subcutaneously in the interscapular region. Measurement of Hemodynamic Parameters and Assessment of Right Ventricular (RV) HypertrophyRV pressure and heart rate were measured, using a pressure transducer connected to a monitor (DynaScope 5100E; Fukuda Denshi, Tokyo, Japan). Right atrial (RA) and RV hypertrophy were evaluated by measuring the ratio of the RA weight to body weight (BW), the ratio of the RV free wall weight to BW, and the ratio of the RV weight to the left ventricular free wall plus septum (LV + IVS) weight. (Received June 19, 2008; revised manuscript received September 8, 2008; accepted September 24, 2008; released online December 26, 2008) Departments of Cardiology, *Physiology, Akita University School of Medicine, Akita, Japan Mailing address: Hiroshi Ito, Department of Ca...

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Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,Land Itoin rapid atrial pacing in rabbits

Abstract: L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

Cited by 105 publications

References 32 publications

Recent advances in the molecular pathophysiology of atrial fibrillation

Recent advances in the molecular pathophysiology of atrial fibrillation

Role of abnormal sarcoplasmic reticulum function in atrial fibrillation

Molecular and Electrical Remodeling of L- and T-Type Ca2+ Channels in Rat Right Atrium With Monocrotaline-Induced Pulmonary Hypertension

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