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Atrial fibrillation is associated with hypermethylation in human left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously hypertensive rats

R. Doñate Puertas 1 E. Meugnier 2 C. Romestaing 3 C. Rey 4 E. Morel 5 J. Lachuer 6 N. Gadot 7 A. Scridon 8 C. Julien F. Tronc B. Chapuis C. Valla 9 A. Janin 9 Luciano Pirola 2 A. Mejat 10 S. Rome 2 Philippe Chevalier 11
1 EA 4612 Neurocardiology Unit
2 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
3 LEHNA - Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés
4 ProfilXpert, Univ-US7 INSERM
Santé Lyon Est - Louis Léopold Ollier
5 Rhythmology Unit Louis Pradel Cardiology Hospital
6 ProfileXpert
7 ANIPATH
8 Physiology Department
9 INMG - Institut NeuroMyoGène
10 LBMC UMR 5239 - Laboratoire de biologie et modélisation de la cellule
11 Unité de Cardiologie et Soins Intensifs
Abstract : Atrial fibrillation (AF) is the most common cardiac arrhythmia. As the molecular mechanisms underlying the pathology are largely unknown, this cardiac arrhythmia remains difficult to treat. To identify specific molecular actors involved in AF, we have performed a transcriptomic analysis on left atrium (LA) from patients with valvular heart disease with or without AF. We showed that 1627 genes had altered basal expression level in LA tissue of AF patients compared with the control group. The significantly enriched gene ontology biological process ‘‘anatomical structure morphogenesis’’ contained the highest number of genes in line with changes in structure that occur when the human heart remodels following AF development (ie, LA dilatation and interstitial fibrosis). We then focused the study on Pitx2 (paired-like homeodomain 2), being the most altered transcription factor in LA from AF patients and from which compelling evidence have indicated that its reduced expression can be considered as a marker for the disease. In addition, its expression was inversely correlated with LA size. We demonstrated that AF is associ- ated with Pitx2 promoter hypermethylation both in humans and arrhythmic aging spontaneously hypertensive rats. Chronic administration of a DNA methylation inhib- itor (ie, 5-Aza-20-deoxycitidine) improved ECG arrhythmic profiles and superoxide dismutase activities and reduced fibrosis in the left ventricle of spontaneously hyper- tensive rats. Taken together, these data support the notion that AF is associated with epigenetic changes in LA and provide a proof-of-concept that hypomethylating agents have to be considered in the treatment of atrial arrhythmias
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Submitted on : Monday, October 23, 2017 - 3:45:05 PM
Last modification on : Friday, January 7, 2022 - 3:43:16 AM

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R. Doñate Puertas, E. Meugnier, C. Romestaing, C. Rey, E. Morel, et al.. Atrial fibrillation is associated with hypermethylation in human left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously hypertensive rats. Translational Research, The Journal of Laboratory and Clinical Medicine, Elsevier, 2017, 184, pp.57 - 67.e5. ⟨10.1016/j.trsl.2017.03.004⟩. ⟨hal-01621517⟩

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