Pitx2 Adjacent Noncoding RNA

Holmes, Andrew P.; Kirchhof, Paulus

doi:10.1161/circep.115.003808

Cited by 7 publications

(3 citation statements)

References 15 publications

(20 reference statements)

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“…This study provided robust evidence that LA PITX2 expression varies in AF patients and that reduced PITX2c expression enhances the antiarrhythmic effects of Na-channel blockers by modulating atrial RMP. The study was partly motivated by the assumption that gene variants on chromosome 4q25 modify PITX2 expression, an assumption that has not been definitively proven 9 , 11 , 44 , 46 . Our analysis ( Table 2 ) and that of others indicate that SNP status does not always correlate with PITX2 levels 47 , 48 .…”

Section: Discussionmentioning

confidence: 99%

PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers

Syeda

Holmes

et al. 2016

Journal of the American College of Cardiology

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124

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BackgroundAntiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Recent data suggested that paired like homeodomain-2 transcription factor (PITX2) might play an important role in regulating gene expression and electrical function of the adult left atrium (LA).ObjectivesAfter determining LA PITX2 expression in AF patients requiring rhythm control therapy, the authors assessed the effects of Pitx2c on LA electrophysiology and the effect of antiarrhythmic drugs.MethodsLA PITX2 messenger ribonucleic acid (mRNA) levels were measured in 95 patients undergoing thoracoscopic AF ablation. The effects of flecainide, a sodium (Na+)-channel blocker, and d,l-sotalol, a potassium channel blocker, were studied in littermate mice with normal and reduced Pitx2c mRNA by electrophysiological study, optical mapping, and patch clamp studies. PITX2-dependent mechanisms of antiarrhythmic drug action were studied in human embryonic kidney (HEK) cells expressing human Na channels and by modeling human action potentials.ResultsFlecainide 1 μmol/l was more effective in suppressing atrial arrhythmias in atria with reduced Pitx2c mRNA levels (Pitx2c+/–). Resting membrane potential was more depolarized in Pitx2c+/– atria, and TWIK-related acid-sensitive K+ channel 2 (TASK-2) gene and protein expression were decreased. This resulted in enhanced post-repolarization refractoriness and more effective Na-channel inhibition. Defined holding potentials eliminated differences in flecainide’s effects between wild-type and Pitx2c+/– atrial cardiomyocytes. More positive holding potentials replicated the increased effectiveness of flecainide in blocking human Nav1.5 channels in HEK293 cells. Computer modeling reproduced an enhanced effectiveness of Na-channel block when resting membrane potential was slightly depolarized.ConclusionsPITX2 mRNA modulates atrial resting membrane potential and thereby alters the effectiveness of Na-channel blockers. PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF.

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Section: Discussionmentioning

confidence: 99%

PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers

Syeda

Holmes

et al. 2016

Journal of the American College of Cardiology

Self Cite

124

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“…One of the genes identified in AF is PITX2, which is also associated with heart development. Holmes et al [ 132 ] found that mice predisposed to developing AF had relatively low levels of PITX2. PITX2 affected cardiac ion channels to alter the atrial refractory period.…”

Section: Lncrnas In Atrial Remodeling and Development Of Afmentioning

confidence: 99%

Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System

Bektik

Cowan

Wang

2020

IJMS

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Atrial fibrillation (AF) is a type of sustained arrhythmia in humans often characterized by devastating alterations to the cardiac conduction system as well as the structure of the atria. AF can lead to decreased cardiac function, heart failure, and other complications. Long non-coding RNAs (lncRNAs) have been shown to play important roles in the cardiovascular system, including AF; however, a large group of lncRNAs is not conserved between mouse and human. Furthermore, AF has complex networks showing variations in mechanisms in different species, making it challenging to utilize conventional animal models to investigate the functional roles and potential therapeutic benefits of lncRNAs for AF. Fortunately, pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) offer a reliable platform to study lncRNA functions in AF because of certain electrophysiological and molecular similarities with native human CMs. In this review, we first summarize the broad aspects of lncRNAs in various heart disease settings, then focus on their potential roles in AF development and pathophysiology. We also discuss current uses of PSCs in AF research and describe how these studies could be developed into novel therapeutics for AF and other cardiovascular diseases.

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“…Additionally, TCONS_00075467 adsorbed miR-328 to derepress the downstream target gene L-type voltage-dependent calcium channel subunit α1C expression to alleviate AF electrical remodeling. Several cardiac-specific transcription factors, such as paired-like homeodomain transcription factor 2 (PITX2) and T-Box transcription factor 5 (TBX5), have been shown to be involved in the regulation of ion channel genes and play a role in AF, with decreasing PITX2 level shortening atrial effective refractory period [ 34 , 35 ]. Gore-Panter et al identified a lncRNA gene localized upstream to the PITX2 gene, called PITX2 adjacent non-coding RNA (PANCR) [ 36 ].…”

Section: Lncrnas and Cardiac Electrical Remodelingmentioning

confidence: 99%