Malgré les progrès considérables cellulaire arythmique commun entre des patients réalisés en termes de compréhension des à fonds génétiques différents atteints de mécanismes à l'origine des maladies du rythme syndrome de Brugada (BrS). Nous avons montré cardiaque, ces dernières restent parmi les qu'IRXS participe à la régulation de la problèmes les plus fréquemment rencontrés en conduction ventriculaire rapide en régulant cardiologie et constituent la principale cause de l'expression de SCNSA et des jonctions gap dans décès. Le dysfonctionnement ou la désexpression les cardiomyocytes humains. En ce qui concerne d'un seul canal ionique peuvent être à l'origine de la BrS, indépendamment du contexte génétique plusieurs types d'arythmies en fonction du fond ou de la présence des mutation SCN5A, les génétique du patient. Les cardiomyocytes dérivées hiPS-CMs ventriculaires issues de patients de cellules souches pluripotentes induites de différents atteints de BrS étaient plus sujets aux l'homme (hiPS-CMs) confèrent un outil précieux arythmies qui étaient associees à une et fiable pour mieux comprendre l'arythmie augmentation du sodium tardif. Globalement, les cardiaque. hiPS-CMs fournissent un outil pertinent pour De là, nous avons défié ce modèle pour modéliser l'arythmie cardiaque humaine, en plus caractériser l'arythmie causée par des mutations de elles confèrent un environnement cellulaire facteur de transcription Iroquois, IRX5, et pour pertinent pour étudier de nouvelles fonctions afin explorer la présence d'un phénotype de développer des pistes thérapeutiques. / Despite considerable advances in the understanding of basic mechanisms involved in the genesis and perpetuation of arrhythmias, cardiac rhythm disorders remain among the most commonly encountered problems and the leading cause of death in cardiology. Dysfunction or misexpression of one single ion channel can be at the root of several types of arrhythmias depending on patient genetic background. Human induced pluripotent stem cells derived cardiomyocytes (hiPS-CMs) confer a valuable and reliable tool to better understand cardiac arrhythmia. Therefore, we challenged this model to characterize arrhythmia caused by missense mutations at the Iroquois transcription factor, IRX5, and to elaborate a common cellular phenotype for Brugada syndrome (BrS) described in patients with different genetic backgrounds. Interestingly, we showed that JRX5 participates in controlling fast ventricular conduction through sustaining SCN5A and gap junction proper expression in human cardiomyocytes. As for BrS, regardless of the genetic background or the presence of SCN5A mutations, ventricular hiPSCMs originated from different BrS patients were more prone to arrhythmias which were associated with increased late sodium. Overall, hiPS-CMs provide a pertinent translational tool to model human cardiac arrhythmia, and they confer a relevant cellular environment to study new functions and therefore develop novel therapeutic tracks.

Irx5 is a homeodomain transcription factor that negatively regulates cardiac fast transient outward K+ currents (Ito,f) via the KV4.2 gene and is thereby a major determinant of the transmural repolarization gradient. While Ito,f is invariably reduced in heart disease and changes in Ito,f can modulate both cardiac contractility and hypertrophy, less is known about a functional role of Irx5, and its relationship with Ito,f, in the normal and diseased heart. Here I show that Irx5 plays crucial roles in the regulation of cardiac contractility and proper adaptive hypertrophy. Specifically, Irx5-deficient (Irx5-/-) hearts had reduced cardiac contractility and lacked the normal regional difference in excitation-contraction with decreased action potential duration, Ca2+ transients and myocyte shortening in sub-endocardial, but not sub-epicardial, myocytes. In addition, Irx5-/- mice showed less cardiac hypertrophy, but increased interstitial fibrosis and greater contractility impairment following pressure overload. A defect in hypertrophic responses in Irx5-/- myocardium was confirmed in cultured neonatal mouse ventricular myocytes, exposed to norepinephrine while being restored with Irx5 replacement. Interestingly, studies using mice virtually lacking Ito,f (i.e. KV4.2-deficient) showed that reduced contractility in Irx5-/- mice was completely restored by loss of KV4.2, whereas hypertrophic responses to pressure-overload in hearts remained impaired when both Irx5 and Ito,f were absent. These findings suggest that Irx5 regulates cardiac contractility in an Ito,f-dependent manner while affecting hypertrophy independent of Ito,f. On the other hand, Irx5-ablation attenuated calcineurin (Cn)-induced hypertrophy in hearts and cultured cardiomyocytes, suggesting that the effect of Irx5 on hypertrophy involves the Cn-NFAT signalling cascade. Biochemical assessments further revealed that Irx5 can positively mediate Cn-NFAT activities as well as Nfatc3 and Gata4 expression, and interacts with Nfatc3 and Gata4, suggesting the formation of a transcription complex for hypertrophic gene regulation. Taken together, these studies have identified Irx5 as a vital cardiac transcription factor, important for contractile function of the heart by regulating Ito,f, and compensatory hypertrophic response to biomechanical stress in the heart by affecting the Cn-NFAT (and Gata4) signaling pathway.

Irx5 is a homeodomain transcription factor that negatively regulates cardiac fast transient outward K+ currents (Ito,f) via the KV4.2 gene and is thereby a major determinant of the transmural repolarization gradient. While Ito,f is invariably reduced in heart disease and changes in Ito,f can modulate both cardiac contractility and hypertrophy, less is known about a functional role of Irx5, and its relationship with Ito,f, in the normal and diseased heart. Here I show that Irx5 plays crucial roles in the regulation of cardiac contractility and proper adaptive hypertrophy. Specifically, Irx5-deficient (Irx5-/-) hearts had reduced cardiac contractility and lacked the normal regional difference in excitation-contraction with decreased action potential duration, Ca2+ transients and myocyte shortening in sub-endocardial, but not sub-epicardial, myocytes. In addition, Irx5-/- mice showed less cardiac hypertrophy, but increased interstitial fibrosis and greater contractility impairment following pressure overload. A defect in hypertrophic responses in Irx5-/- myocardium was confirmed in cultured neonatal mouse ventricular myocytes, exposed to norepinephrine while being restored with Irx5 replacement. Interestingly, studies using mice virtually lacking Ito,f (i.e. KV4.2-deficient) showed that reduced contractility in Irx5-/- mice was completely restored by loss of KV4.2, whereas hypertrophic responses to pressure-overload in hearts remained impaired when both Irx5 and Ito,f were absent. These findings suggest that Irx5 regulates cardiac contractility in an Ito,f-dependent manner while affecting hypertrophy independent of Ito,f. On the other hand, Irx5-ablation attenuated calcineurin (Cn)-induced hypertrophy in hearts and cultured cardiomyocytes, suggesting that the effect of Irx5 on hypertrophy involves the Cn-NFAT signalling cascade. Biochemical assessments further revealed that Irx5 can positively mediate Cn-NFAT activities as well as Nfatc3 and Gata4 expression, and interacts with Nfatc3 and Gata4, suggesting the formation of a transcription complex for hypertrophic gene regulation. Taken together, these studies have identified Irx5 as a vital cardiac transcription factor, important for contractile function of the heart by regulating Ito,f, and compensatory hypertrophic response to biomechanical stress in the heart by affecting the Cn-NFAT (and Gata4) signaling pathway.