Similar Datasets
Project description:Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology.
| S-EPMC6200419 | biostudies-literature
Project description:Several inherited arrhythmias primarily affect the right ventricle, including Brugada syndrome and arrhythmogenic cardiomyopathy, however the molecular basis of this chamber predilection is not well understood. Right and left ventricular cardiomyocytes derive from distinct progenitor populations. Here, we show that Hrt2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle and Notch signaling in the left ventricle. Perturbations of Wnt and Notch signaling during development and in the adult lead to chamber-specific transcriptional effects on Hrt2 expression associated with distinct binding patterns to Hrt2 enhancers. Differential enhancer binding is present at early developmental stages when the signaling pathways are active and persists into adulthood. Consistent with chamber-specific regulation, mice deficient in Wnt transcriptional activity dysregulate only a small fraction of transcripts in common between ventricles. Wnt target gen es important for cellular electrophysiology are differentially regulated, resulting in perturbed cardiac conduction and cellular electrophysiological parameters only within the right ventricle. Ex vivo and in vivo physiologic stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. Taken together, these data delineate mechanisms underlying ventricular-specific arrhythmia susceptibility due to embryonic programming.
2018-12-14 | GSE106507 | GEO
Project description:Several inherited arrhythmias primarily affect the right ventricle, including Brugada syndrome and arrhythmogenic cardiomyopathy, however the molecular basis of this chamber predilection is not well understood. Right and left ventricular cardiomyocytes derive from distinct progenitor populations. Here, we show that Hrt2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle and Notch signaling in the left ventricle. Perturbations of Wnt and Notch signaling during development and in the adult lead to chamber-specific transcriptional effects on Hrt2 expression associated with distinct binding patterns to Hrt2 enhancers. Differential enhancer binding is present at early developmental stages when the signaling pathways are active and persists into adulthood. Consistent with chamber-specific regulation, mice deficient in Wnt transcriptional activity dysregulate only a small fraction of transcripts in common between ventricles. Wnt target gen es important for cellular electrophysiology are differentially regulated, resulting in perturbed cardiac conduction and cellular electrophysiological parameters only within the right ventricle. Ex vivo and in vivo physiologic stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. Taken together, these data delineate mechanisms underlying ventricular-specific arrhythmia susceptibility due to embryonic programming.
2018-12-14 | GSE106506 | GEO
Project description:Differential Wnt-mediated Programming and Arrhythmogenesis in Right versus Left Ventricles
| PRJNA417059 | ENA
Project description:Differential Wnt-mediated Programming and Arrhythmogenesis in Right versus Left Ventricles [wntlof]
| PRJNA417071 | ENA
Project description:Differential Wnt-mediated Programming and Arrhythmogenesis in Right versus Left Ventricles [wntgof]
| PRJNA417134 | ENA
Project description:BackgroundThough long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models.Methodology/principal findingsUsing a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression.Conclusions/significanceThe differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation.
| S-EPMC3098252 | biostudies-literature
Project description:The aim of the present study was to investigate the differential expression of B‑type natriuretic peptide (BNP) between the left and right ventricle (RV) in sudden cardiac death (SCD). A total of 26 forensic autopsy cases of sudden death (survival time <30 min, postmortem interval <48 h or frozen within 6 h following death) in the present institute were examined. The cases consisted of acute ischemic heart disease (AIHD, n=15) with/without apparent myocardial necrosis as a sign of infarction (acute myocardial infarction, n=6; ischemic heart disease, IHD, n=9), and arrhythmogenic right ventricular cardiomyopathy (ARVC/D, n=5), in addition to traffic accidents and high falls without any pre existing heart disease as control (C, total n=6). BNP was investigated in all cases by the colloidal gold method, hematoxylin‑eosin staining, immunohistochemistry (IHC) and the molecular pathological method. The IHC results demonstrated that a positive BNP immunostaining was detected in all groups; however, there was no difference between different causes of death. Pericardial N‑terminal (NT)‑proBNP concentration was significantly increased in deaths resulting from AIHD and ARVC/D compared with control group. The relative quantification of BNP mRNA demonstrated that relative expression levels of BNP mRNA were significantly increased in the left ventricle (LV) in the AIHD group, and in the RV of the ARVC/D group. The relative quantification difference and ratio of BNP mRNA between LV and RV demonstrated a significantly greater value in the AIHD group compared with control group. BNP mRNA in myocardium and NT‑proBNP concentration in pericardial fluid were elevated in SCD patients, and left ventricular dysfunction predominated in AIHD patients, whereas right ventricular dysfunction predominated in ARVC/D patients. The results of the present study suggest the possible use of molecular pathology of BNP for the determination of terminal cardiac function in SCD and analysis of its fatal mechanism in forensic practice.
| S-EPMC5647027 | biostudies-literature
Project description:The right and left ventricles have traditionally been studied as individual entities. Furthermore, modifications found in diseased left ventricles are assumed to influence on right ventricle alterations, but the connection is poorly understood. In this review, we describe the differences between ventricles under physiological and pathological conditions. Understanding the mechanisms that differentiate both ventricles would facilitate a more effective use of therapeutics and broaden our knowledge of right ventricle (RV) dysfunction. RV failure is the strongest predictor of mortality in pulmonary arterial hypertension, but at present, there are no definitive therapies directly targeting RV failure. We further explore the current state of drugs and molecules that improve RV failure in experimental therapeutics and clinical trials to treat pulmonary arterial hypertension and provide evidence of their potential benefits in heart failure.
| S-EPMC8421158 | biostudies-literature
Project description:Mirabegron increases atrial fibrillation (AF) risk. The left atrium (LA) is the most critical 'substrate' for AF and has higher arrhythmogenesis compared with the right atrium (RA). The present study aimed to investigate the electrophysiological and arrhythmogenic effects of mirabegron on the LA and RA and clarify the potential underlying mechanisms. Conventional microelectrodes, a whole-cell patch clamp and a confocal microscope were used in rabbit LA and RA preparations or single LA and RA myocytes before and after mirabegron administration with or without cotreatment with KT5823 [a cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor]. The baseline action potential duration at repolarization extents of 20 and 50% (but not 90%) were shorter in the LA than in the RA. Mirabegron at 0.1 and 1 µM (but not 0.01 µM) reduced the action potential duration at repolarization extents of 20 and 50% in the LA and RA. Mirabegron (0.1 µM) increased the occurrence of tachypacing-induced burst firing in the LA but not in the RA, where it was suppressed by KT5823 (1 µM). Mirabegron (0.1 µM) increased the L-type Ca2+ current (ICa-L), ultrarapid component of delayed rectifier K+ current (IKur), Ca2+ transients and sarcoplasmic reticulum Ca2+ content but reduced transient outward K+ current (Ito) in the LA myocytes. However, mirabegron did not change the Na+ current and delayed rectifier K+ current in the LA myocytes. Moreover, pretreatment with KT5823 (1 µM) inhibited the effects of mirabegron on ICa-L, Ito and IKur in the LA myocytes. Furthermore, in the RA myocytes, mirabegron reduced ICa-L but did not change Ito. In conclusion, mirabegron differentially regulates electrophysiological characteristics in the LA and RA. Through the activation of the cAMP-dependent protein kinase pathway and induction of Ca2+ dysregulation, mirabegron may increase LA arrhythmogenesis, leading to increased AF risk.
| S-EPMC9627121 | biostudies-literature