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Project description:Sudden cardiac death is the number one cause of death worldwide. Major causes of sudden cardiac death include myocardial infarction and cardiomyopathies. To develop novel therapeutic strategies, we need to identify key factors that are required for proper cardiac function and are dysregulated in the diseased heart. Under this notion, we found T-box 5 (TBX5), a transcription factor regarded solely in the context of congenital heart disease, to be downregulated in human diseased left ventricles. To investigate the effects of TBX5 loss in the adult heart, we generated an inducible ventricular cardiomyocyte specific knock-out mouse model (vTbx5KO). We performed integrative genome-wide chromatin occupancy and transcriptomic analysis and identified 47 downregulated transcripts in vTbx5KO that contain TBX5 active enhancers. The TBX5 targets in the ventricle included genes implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5) as well as cardiac protection upon stress (Fhl2, Gpr22, Fgf16). In line with this analysis, vTbx5KO mice presented cardiac conduction defects and arrhythmias at baseline as well as exacerbated cardiac remodeling upon Angiotensin II-induced hypertrophy. In conclusion, this study uncovers a novel protective role of TBX5 upon cardiac remodeling and renders TBX5 as an interesting therapeutic target.
2020-07-19 | GSE101614 | GEO
Project description:Sudden cardiac death is the number one cause of death worldwide. Major causes of sudden cardiac death include myocardial infarction and cardiomyopathies. To develop novel therapeutic strategies, we need to identify key factors that are required for proper cardiac function and are dysregulated in the diseased heart. Under this notion, we found T-box 5 (TBX5), a transcription factor regarded solely in the context of congenital heart disease, to be downregulated in human diseased left ventricles. To investigate the effects of TBX5 loss in the adult heart, we generated an inducible ventricular cardiomyocyte specific knock-out mouse model (vTbx5KO). We performed integrative genome-wide chromatin occupancy and transcriptomic analysis and identified 47 downregulated transcripts in vTbx5KO that contain TBX5 active enhancers. The TBX5 targets in the ventricle included genes implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5) as well as cardiac protection upon stress (Fhl2, Gpr22, Fgf16). In line with this analysis, vTbx5KO mice presented cardiac conduction defects and arrhythmias at baseline as well as exacerbated cardiac remodeling upon Angiotensin II-induced hypertrophy. In conclusion, this study uncovers a novel protective role of TBX5 upon cardiac remodeling and renders TBX5 as an interesting therapeutic target.
2020-07-19 | GSE101613 | GEO
Project description:Ventricular T-box 5 in the adult heart ensures normal cardiac conduction and protects from pathologic cardiac remodeling
| PRJNA394989 | ENA
Project description:Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24 ± 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure.
| S-EPMC6188225 | biostudies-literature
Project description:BackgroundMutations of the transcription factor Nkx2-5 cause pleiotropic heart defects with incomplete penetrance. This variability suggests that additional factors can affect or prevent the mutant phenotype. We assess here the role of genetic modifiers and their interactions.Methods and resultsHeterozygous Nkx2-5 knockout mice in the inbred strain background C57Bl/6 frequently have atrial and ventricular septal defects. The incidences are substantially reduced in the Nkx2-5(+/-) progeny of first-generation (F1) outcrosses to the strains FVB/N or A/J. Defects recur in the second generation (F2) of the F1 X F1 intercross or backcrosses to the parental strains. Analysis of >3000 Nkx2-5(+/-) hearts from 5 F2 crosses demonstrates the profound influence of genetic modifiers on disease presentation. On the basis of their incidences and coincidences, anatomically distinct malformations have shared and unique modifiers. All 3 strains carry susceptibility alleles at different loci for atrial and ventricular septal defects. Relative to the other 2 strains, A/J carries polymorphisms that confer greater susceptibility to atrial septal defect and atrioventricular septal defects and C57Bl/6 to muscular ventricular septal defects. Segregation analyses reveal that > or = 2 loci influence membranous ventricular septal defect susceptibility, whereas > or = loci and at least 1 epistatic interaction affect muscular ventricular and atrial septal defects.ConclusionsAlleles of modifier genes can either buffer perturbations on cardiac development or direct the manifestation of a defect. In a genetically heterogeneous population, the predominant effect of modifier genes is health. (Circulation. 2010;121:1313-1321.)
| S-EPMC2953850 | biostudies-literature
Project description:RationaleThe heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood.ObjectiveTo study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning.Methods and resultsUsing mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5, and T-box transcriptional repressor, Tbx3, determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS.ConclusionsThe CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.
| S-EPMC8328577 | biostudies-literature
Project description:BackgroundAccumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.MethodsTwo independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet.ResultsThe KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values.ConclusionsChronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.
| S-EPMC7819534 | biostudies-literature
Project description:Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy.We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (heart failure, n=10) and nonfailing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. Heart failure produced heterogeneous prolongation of action potential duration resulting in the decrease of transmural action potential duration dispersion (64 ± 12 ms versus 129 ± 15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39 ± 3 cm/s versus 49 ± 2 cm/s in NF, P=0.008) to the epicardium (28 ± 3 cm/s versus 40 ± 2 cm/s in NF, P=0.008). Conduction slowing was likely due to connexin 43 (Cx43) downregulation, decreased colocalization of Cx43 with N-cadherin (40 ± 2% versus 52 ± 5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wave breaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in heart failure 16.4 ± 7.7 versus 9.9 ± 1.4% in NF, P=0.02).Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with nonischemic cardiomyopathy.
| S-EPMC3351089 | biostudies-literature
Project description:Systemic inhibition of miR-21 has proven effective against myocardial fibrosis and dysfunction, while studies in cardiac myocytes suggested a protective role in this cell type. Considering potential implications for therapy, we aimed to determine the cell fraction where miR-21 exerts its pathological activity. We developed a viral vector-based strategy for gene targeting of nonmyocyte cardiac cells in vivo and compared global to cardiac myocyte-specific and nonmyocyte-specific deletion of miR-21 in chronic left ventricular pressure overload. Murine moloney virus and serotype 9 of adeno-associated virus were engineered to encode improved Cre recombinase for genetic deletion in miR-21fl/fl mice. Pericardial injection of murine moloney virus-improved Cre recombinase to neonates achieved highly selective genetic ablation of miR-21 in nonmyocyte cardiac cells, identified as cardiac fibroblasts and endothelial cells. Upon left ventricular pressure overload, cardiac function was only preserved in mice with miR-21 deficiency in nonmyocyte cardiac cells, but not in mice with global or cardiac myocyte-specific ablation. Our data demonstrate that miR-21 exerts its pathologic activity directly in cardiac nonmyocytes and encourage further development of antimiR-21 therapy toward cellular tropism.
| S-EPMC5154480 | biostudies-literature
Project description:Sarcomeres are the basic contractile units of cardiac myocytes. Recent studies demonstrated remodeling of sarcomeric proteins in several diseases, including genetic defects and heart failure. Here we investigated remodeling of sarcomeric ?-actinin in two models of heart failure, synchronous (SHF) and dyssynchronous heart failure (DHF), as well as a model of cardiac resynchronization therapy (CRT). We applied three-dimensional confocal microscopy and quantitative methods of image analysis to study isolated cells from our animal models. 3D Fourier analysis revealed a decrease of the spatial regularity of the ?-actinin distribution in both SHF and DHF versus control cells. The spatial regularity of ?-actinin in DHF cells was reduced when compared with SHF cells. The spatial regularity of ?-actinin was partially restored after CRT. We found longitudinal depositions of ?-actinin in SHF, DHF and CRT cells. These depositions spanned adjacent Z-disks and exhibited a lower density of ?-actinin than in the Z-disk. Differences in the occurrence of depositions between the SHF, CRT and DHF models versus control were significant. Also, CRT cells exhibited a higher occurrence of depositions versus SHF, but not DHF cells. Other sarcomeric proteins did not accumulate in the depositions to the same extent as ?-actinin. We did not find differences in the expression of ?-actinin protein and its encoding gene in our animal models. In summary, our studies indicate that HF is associated with two different types of remodeling of ?-actinin and only one of those was reversed after CRT. We suggest that these results can guide us to an understanding of remodeling of structures and function associated with sarcomeres.
| S-EPMC4077200 | biostudies-literature