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

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.

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Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8050048 ◽

2021 ◽

Vol 8 (5) ◽

pp. 48

Author(s):

Drew Nassal ◽

Jane Yu ◽

Dennison Min ◽

Cemantha Lane ◽

Rebecca Shaheen ◽

...

Keyword(s):

Ion Channels ◽

Cardiac Disease ◽

Conduction System ◽

Cytoskeletal Proteins ◽

Cardiac Conduction ◽

Proper Function ◽

Cardiac Conduction System ◽

Loss Of Function ◽

Macromolecular Complexes ◽

Conduction Disturbances

The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout the conduction system. Importantly, inherited or acquired defects in a wide class of ion channels has been linked to dysfunction at various stages of the conduction system resulting in life-threatening cardiac arrhythmia. There is growing appreciation of the role that adapter and cytoskeletal proteins play in organizing ion channel macromolecular complexes critical for proper function of the cardiac conduction system. In particular, members of the ankyrin and spectrin families have emerged as important nodes for normal expression and regulation of ion channels in myocytes throughout the conduction system. Human variants impacting ankyrin/spectrin function give rise to a broad constellation of cardiac arrhythmias. Furthermore, chronic neurohumoral and biomechanical stress promotes ankyrin/spectrin loss of function that likely contributes to conduction disturbances in the setting of acquired cardiac disease. Collectively, this review seeks to bring attention to the significance of these cytoskeletal players and emphasize the potential therapeutic role they represent in a myriad of cardiac disease states.

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

Circulation Research ◽

10.1161/res.129.suppl_1.mp239 ◽

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.

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2011 Riley Heart Center Symposium on Cardiac Development: Development of the Cardiac Conduction System and Arrhythmias

Pediatric Cardiology ◽

10.1007/s00246-012-0313-9 ◽

2012 ◽

Vol 33 (6) ◽

pp. 879-881

Author(s):

Michael Rubart ◽

Randall L. Caldwell ◽

Peng-Sheng Chen ◽

Weinian Shou

Keyword(s):

Cardiac Development ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Heart Center

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Role of Homeodomain-Only Protein in the Cardiac Conduction System

Trends in Cardiovascular Medicine ◽

10.1016/j.tcm.2006.03.009 ◽

2006 ◽

Vol 16 (6) ◽

pp. 193-198 ◽

Cited By ~ 3

Author(s):

Fang Liu ◽

Fraz A. Ismat ◽

Vickas V. Patel

Keyword(s):

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System

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THE ROLE OF AUTOANTIBODIES IN VARIOUS CELLULAR AND INTRACELLULAR CARDIAC STRUCTURES IN CHILDREN WITH HEART RHYTHM DISTURBANCES (A REVIEW)

Complex Issues of Cardiovascular Diseases ◽

10.17802/2306-1278-2019-8-3-96-103 ◽

2019 ◽

Vol 8 (3) ◽

pp. 96-103 ◽

Cited By ~ 1

Author(s):

I. V. Plotnikova ◽

L. I. Svintsova ◽

O. Yu. Dzhaffarova

Keyword(s):

Immune Status ◽

Heart Rhythm ◽

Conduction System ◽

Cardiac Conduction ◽

Autoimmune Response ◽

Cardiac Conduction System ◽

Childhood And Adolescence ◽

Conduction Disorders ◽

Intracellular Proteins

This review discusses the role of autoimmune mechanisms in the development of heart rhythm disturbances and conduction disorders of various origins. The search was performed using PubMed, Medline and Google Scholar. Specific cardiovascular diseases (dilated cardiomyopathy, myocarditis, conduction disorders) developing in childhood and adolescence are associated with an increase in titer to intracellular proteins specific to myocardiocytes and cells of the cardiac conduction system. Candidate autoantibodies markers for autoimmune response have been selected. The rationale for analyzing the immune status of heart rhythm disturbances in children and adolescents has been provided.

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Role of the Cardiac Conduction System in Determining the QRS Amplitude after Bleeding

Cardiology ◽

10.1159/000169674 ◽

1974 ◽

Vol 59 (3) ◽

pp. 162-171 ◽

Cited By ~ 2

Author(s):

Mordechai Manoach ◽

Edith Grosman ◽

Daliah Varon ◽

Nissim Kauli ◽

Simon Gitter ◽

...

Keyword(s):

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System

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

Circulation ◽

10.1161/circ.130.suppl_2.15973 ◽

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.

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