A context-specific cardiac ß-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart.

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675-ß-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-ß-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of ß-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2-5 and GATA4 in stabilized-ß-catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/ß-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing ß-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/ß-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway.

Atrial fibrillation and heart failure-associated remodeling of two-pore-domain potassium (K2P) channels in murine disease models: focus on TASK-1.

Understanding molecular mechanisms involved in atrial tissue remodeling and arrhythmogenesis in atrial fibrillation (AF) is essential for developing specific therapeutic approaches. Two-pore-domain potassium (K2P) channels modulate cellular excitability, and TASK-1 (K2P3.1) currents were recently shown to alter atrial action potential duration in AF and heart failure (HF). Finding animal models of AF that closely resemble pathophysiological alterations in human is a challenging task. This study aimed to analyze murine cardiac expression patterns of K2P channels and to assess modulation of K2P channel expression in murine models of AF and HF. Expression of cardiac K2P channels was quantified by real-time qPCR and immunoblot in mouse models of AF [cAMP-response element modulator (CREM)-IbΔC-X transgenic animals] or HF (cardiac dysfunction induced by transverse aortic constriction, TAC). Cloned murine, human, and porcine TASK-1 channels were heterologously expressed in Xenopus laevis oocytes. Two-electrode voltage clamp experiments were used for functional characterization. In murine models, among members of the K2P channel family, TASK-1 expression displayed highest levels in both atrial and ventricular tissue samples. Furthermore, K2P2.1, K2P5.1, and K2P6.1 showed significant expression levels. In CREM-transgenic mice, atrial expression of TASK-1 was significantly reduced in comparison with wild-type animals. In a murine model of TAC-induced pressure overload, ventricular TASK-1 expression remained unchanged, while atrial TASK-1 levels were significantly downregulated. When heterologously expressed in Xenopus oocytes, currents of murine, porcine, and human TASK-1 displayed similar characteristics. TASK-1 channels display robust cardiac expression in mice. Murine, porcine, and human TASK-1 channels share functional similarities. Dysregulation of atrial TASK-1 expression in murine AF and HF models suggests a mechanistic contribution to arrhythmogenesis.

Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control.

AIMS: Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias. METHODS AND RESULTS: We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA-sequencing of a ventricular-specific TBX5KO mouse and TBX5 chromatin immunoprecipitation was used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein-level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced. CONCLUSIONS: This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia.

A Three-Dimensional Movement Analysis of the Spike in Fistball.

Due to its relevancy to point scoring, the spike is considered as one of the most important skills in fistball. Biomechanical analyses of this sport are very rare. In the present study, we performed a three-dimensional kinematic analysis of the fistball spike, which helps to specify performance parameters on a descriptive level. Recorded by four synchronized cameras (120 Hz) and linked to the motion capture software Simi Motion® 5.0, three female fistball players of the second German league (24⁻26 years, 1.63⁻1.69 m) performed several spikes under standardized conditions. Results show that the segment velocities of the arm reached their maximum successively from proximal to distal, following the principle of temporal coordination of single impulses. The wrist shows maximum speed when the fist hits the ball. The elbow joint angle performs a rapid transition from a strong flexion to a (almost) full extension; however, the extension is completed after the moment of ball impact. In contrast, the shoulder joint angle increases almost linearly until the fistball contact and decreases afterward. The findings can be used to optimize the training of the spike.