Abstract 15973: miRNA-Hippo Pathway Plays a Critical Role in the Cardiac Conduction System

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jun Wang ◽  
Sylvia Evans ◽  
James Martin
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Critical Role ◽  
Size Control ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Critical Function

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and the CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting the CCS regeneration to facilitate developing efficient cardiovascular therapies. MicroRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in the CCS. Specific disruption of either miR-17-92 or Hippo signaling in the CCS gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through directly repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using Yap antibody, the Hippo signaling effector, which data suggested that Hippo signaling regulates genes involved in the CCS homeostasis. Together, our data indicate a novel miR-Hippo genetic pathway plays critical function in the CCS.

Abstract 260: A miRNA-Hippo Pathway Promotes Cardiac Conduction System Regeneration

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jun Wang ◽  
James F Martin
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Non Coding Rnas

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting CCS regeneration to facilitate developing efficient cardiovascular therapies. microRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in CCS. Disruption of either miR-17-92 or Hippo signaling in heart gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using YAP, the Hippo signaling effector, which suggested that Hippo signaling regulates genes involved in CCS homeostasis. Together, we propose a novel miR-Hippo genetic pathway that promotes CCS regeneration.

Abstract MP239: Hippo Signaling Pathway Maintains Homeostasis Of The Cardiac Conduction System

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Mingjie Zheng ◽  
Jun Wang
Keyword(s):  
Signaling Pathway ◽  
Calcium Homeostasis ◽  
Cardiac Arrhythmias ◽  
Critical Role ◽  
Conduction System ◽  
Conditional Knockout ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. The fundamental Hippo signaling pathway plays critical roles in the heart, yet its role in the CCS remains largely unknown. Here, we found that conditional knockout (CKO) of Hippo signaling kinases Lats1 and Lats2 in the CCS using Hcn4 CreERT2 , led to cardiac arrhythmias in adult mice. Compared with controls, Lats1/2 CKO mutant mice had disrupted calcium homeostasis, increased fibrosis and more fibroblast proliferation in the sinoatrial node. Deletion of the Hippo signaling effectors Yap and Taz in the CCS rescued phenotypes caused by Lats1/2 deletion, and these mice had rescued sinus rhythm and reduced fibrosis, which indicated that Lats1/2 function through Yap and Taz in CCS. Our Cleavage Under Targets and Tagmentation (CUT&Tag)-sequencing using Yap antibody followed by RNA-Seq revealed that Yap directly regulates calcium homeostasis genes such as Ryr2 and fibrosis induction genes such as TGF-β family. Further, we discovered that miR-17-92 represses Hippo signaling by directly suppressing Lats2 expression. miR-17-92 CKO in the CCS led to increased Hippo signaling activity and cardiac arrhythmias, indicating that a fine-tuned level of Hippo signaling is critical for CCS homeostasis. Together, our findings reveal the critical role of a miR-Hippo-Yap genetic pathway in maintaining CCS homeostasis.

Abstract 16005: Highly Efficient Derivation of Human Pacemaker Cells From Pluripotent Stem Cells in Chemically Defined Conditions

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zaniar Ghazizadeh ◽  
Seyedeh Faranak Fattahi ◽  
Mehdi Sharifi-tabar ◽  
Shahab Mirshahvaladi ◽  
Parisa Shabani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Substantial Contribution ◽  
Cardiac Conduction System ◽  
Pacemaker Cells

The cardiac conduction system is a complex network of cells that together orchestrate the rhythmic and coordinated depolarization of the heart. Dysfunction of the cardiac conduction system plays a central role in the pathogenesis of arrhythmia. While much progress has been made understanding cardiomyocyte differentiation, the molecular mechanisms regulating the specification and patterning of cells that form this conductive network is largely unknown. The LIM-homeodomain transcription factor ISL1 is highly expressed in the secondary heart field (SHF) progenitor population that makes a substantial contribution to the developing heart, comprising most cells in the right ventricle, both atria and pacemaker cells. Pacemaker cells comprise the most proximal component of the cardiac conduction system, which have been proposed as the source of most arrhythmogenic events. Their dominance on other spontaneous beating cell types makes them a suitable target for pharmacologic compounds, making access to this cell lineage necessary for the study of new therapeutic agents. To identify the signaling pathways that control the differentiation of human embryonic stem cell (hESC)-derived SHF cells into pacemaker cells, we performed RNA sequencing to compare the hESC-derived ISL1 + population, non-enriched population and undifferentiated hESCs. Furthermore, using a small molecule screen we identified compounds that can improve differentiation of hESCs toward pacemaker cells. Pathway analysis identified the Wnt pathway as the most significant regulator of SHF specification. Further differentiation of human pluripotent stem cells by stage-specific activation of BMP and WNT signaling pathways resulted in phenotypic pacemaker cells, which display morphological characteristics. More than 80% of these cells stained positively for HCN4, Contactin2(CNTN2) and GATA6, key markers of pacemaker cells. The differentiated cells express pacemaker markers, including CNTN2, TBX2, TBX3, HCN4, TBX18, GATA6 indicated by qRT-PCR. They show inward potassium currents through HCN channels in patch clamp experiments. Our data provides a new strategy to obtain human cardiac conduction cells in large scale for disease modeling, drug screening and cell therapy.

scholarly journals PRC1 Stabilizes Cardiac Contraction by Regulating Cardiac Sarcomere Assembly and Cardiac Conduction System Construction

2021 ◽  
Vol 22 (21) ◽  
pp. 11368
Author(s):  
Xixia Peng ◽  
Gang Feng ◽  
Yanyong Zhang ◽  
Yuhua Sun
Keyword(s):  
Cardiac Development ◽  
Critical Role ◽  
Conduction System ◽  
Cardiac Contraction ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Cardiac Sarcomere

Cardiac development is a complex process that is strictly controlled by various factors, including PcG protein complexes. Several studies have reported the critical role of PRC2 in cardiogenesis. However, little is known about the regulation mechanism of PRC1 in embryonic heart development. To gain more insight into the mechanistic role of PRC1 in cardiogenesis, we generated a PRC1 loss-of-function zebrafish line by using the CRISPR/Cas9 system targeting rnf2, a gene encoding the core subunit shared by all PRC1 subfamilies. Our results revealed that Rnf2 is not involved in cardiomyocyte differentiation and heart tube formation, but that it is crucial to maintaining regular cardiac contraction. Further analysis suggested that Rnf2 loss-of-function disrupted cardiac sarcomere assembly through the ectopic activation of non-cardiac sarcomere genes in the developing heart. Meanwhile, Rnf2 deficiency disrupts the construction of the atrioventricular canal and the sinoatrial node by modulating the expression of bmp4 and other atrioventricular canal marker genes, leading to an impaired cardiac conduction system. The disorganized cardiac sarcomere and defective cardiac conduction system together contribute to defective cardiac contraction. Our results emphasize the critical role of PRC1 in the cardiac development.

Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage

Development ◽  
1999 ◽  
Vol 126 (22) ◽  
pp. 5041-5049 ◽  
Author(s):  
G. Cheng ◽  
W.H. Litchenberg ◽  
G.J. Cole ◽  
T. Mikawa ◽  
R.P. Thompson ◽  
...  
Keyword(s):  
Time Course ◽  
Molecular Mechanisms ◽  
Selection Process ◽  
Conduction System ◽  
Lineage Tracing ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Cardiac Tissues ◽  
Cardiac Pacemaking ◽  
Peripheral Cells

The cardiac pacemaking and conduction system sets and maintains the rhythmic pumping action of the heart. Previously, we have shown that peripheral cells of the conduction network in chick (periarterial Purkinje fibers) are selected within a cardiomyogenic lineage and that this recruitment occurs as a result of paracrine cues from coronary arteries. At present, the cellular derivation of other elements of this specialized system (e.g. the nodes and bundles of the central conduction system) are controversial, with some proposing that the evidence supports a neurogenic and others a myogenic origin for these tissues. While such ontological questions remain, it is unlikely that progress can be made on the molecular mechanisms governing patterning and induction of the central conduction system. Here, we have undertaken lineage-tracing strategies based on the distinct properties of replication-incompetent adenoviral and retroviral lacZ-expressing constructs. Using these complementary approaches, it is shown that cells constituting both peripheral and central conduction tissues originate from cardiomyogenic progenitors present in the looped, tubular heart with no detectable contribution by migratory neuroectoderm-derived populations. Moreover, clonal analyses of retrovirally infected cells incorporated within any part of the conduction system suggest that such cells share closer lineage relationships with nearby contractive myocytes than with other, more distal elements of the conduction system. Differentiation birthdating by label dilution using [(3)H]thymidine also demonstrates the occurrence of ongoing myocyte conscription to conductive specialization and provides a time course for this active and localized selection process in different parts of the system. Together, these data suggest that the cardiac conduction system does not develop by outgrowth from a prespecified pool of ‘primary’ myogenic progenitors. Rather, its assembly and elaboration occur via processes that include progressive and localized recruitment of multipotent cardiomyogenic cells to the developing network of specialized cardiac tissues.

scholarly journals Sudden Unexpected Death Associated with Arrhythmogenic Cardiomyopathy: Study of the Cardiac Conduction System

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1323
Author(s):  
Giulia Ottaviani ◽  
Graziella Alfonsi ◽  
Simone G. Ramos ◽  
L. Maximilian Buja
Keyword(s):  
Fibromuscular Dysplasia ◽  
Ventricular Myocardium ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Future Research ◽  
Cardiac Conduction System ◽  
Arrhythmogenic Cardiomyopathy ◽  
Unexpected Death ◽  
The Past ◽  
The Right

A retrospective study was conducted on pathologically diagnosed arrhythmogenic cardiomyopathy (ACM) from consecutive cases over the past 34 years (n = 1109). The anatomo-pathological analyses were performed on 23 hearts diagnosed as ACM (2.07%) from a series of 1109 suspected cases, while histopathological data of cardiac conduction system (CCS) were available for 15 out of 23 cases. The CCS was removed in two blocks, containing the following structures: Sino-atrial node (SAN), atrio-ventricular junction (AVJ) including the atrio-ventricular node (AVN), the His bundle (HB), the bifurcation (BIF), the left bundle branch (LBB) and the right bundle branch (RBB). The ACM cases consisted of 20 (86.96%) sudden unexpected cardiac death (SUCD) and 3 (13.04%) native explanted hearts; 16 (69.56%) were males and 7 (30.44%) were females, ranging in age from 5 to 65 (mean age ± SD, 36.13 ± 16.06) years. The following anomalies of the CCS, displayed as percentages of the 15 ACM SUCD cases in which the CCS has been fully analyzed, have been detected: Hypoplasia of SAN (80%) and/or AVJ (86.67%) due to fatty-fibrous involvement, AVJ dispersion and/or septation (46.67%), central fibrous body (CFB) hypoplasia (33.33%), fibromuscular dysplasia of SAN (20%) and/or AVN (26.67%) arteries, hemorrhage and infarct-like lesions of CCS (13.33%), islands of conduction tissue in CFB (13.33%), Mahaim fibers (13.33%), LBB block by fibrosis (13.33%), AVN tongue (13.33%), HB duplicity (6.67%%), CFB cartilaginous meta-hyperplasia (6.67%), and right sided HB (6.67%). Arrhythmias are the hallmark of ACM, not only from the fatty-fibrous disruption of the ventricular myocardium that accounts for reentrant ventricular tachycardia, but also from the fatty-fibrous involvement of CCS itself. Future research should focus on application of these knowledge on CCS anomalies to be added to diagnostic criteria or at least to be useful to detect the patients with higher sudden death risks.

Sign in / Sign up

Export Citation Format

Share Document