scholarly journals Transcriptome profile of the sinoatrial ring reveals conserved and novel genetic programs of the zebrafish pacemaker

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Rashid Minhas ◽  
Henry Loeffler-Wirth ◽  
Yusra H. Siddiqui ◽  
Tomasz Obrębski ◽  
Shikha Vashisht ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Heart Development ◽  
Heart Diseases ◽  
Cardiac Conduction ◽  
Molecular Profile ◽  
Signature Genes ◽  
Pacemaker Function ◽  
Genes Encoding ◽  
Electrical Impulses ◽  
Functional Analyses

Abstract Background Sinoatrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. The SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although the SAN pacemaker has been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Results To characterize the molecular profile of the zebrafish sinoatrial ring (SAR) and elucidate the mechanism of pacemaker function, we utilized the transgenic line sqet33mi59BEt to isolate cells of the SAR of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways involved in pacemaker development. We show that, compared to the rest of the heart, the zebrafish SAR overexpresses several mammalian SAN pacemaker signature genes, which include hcn4 as well as those encoding calcium- and potassium-gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases, which suggest the relevance of our transcriptomics resource to studying human heart conditions. Finally, functional analyses of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, uncovered their novel role in heart development and physiology. Conclusion Our results established conserved aspects between zebrafish and mammalian pacemaker function and revealed novel factors implicated in maintaining cardiac rhythm. The transcriptome data generated in this study represents a unique and valuable resource for the study of pacemaker function and associated heart diseases.

scholarly journals Transcriptome Profile of the Sinoatrial Ring Reveals Conserved and Novel Genetic Programs of the Zebrafish Pacemaker

2020 ◽  
Author(s):  
Rashid Minhas ◽  
Henry Loeffler-Wirth ◽  
Yusra Siddiqui ◽  
Tomasz Obrebski ◽  
Shikha Vhashist ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Heart Development ◽  
Heart Diseases ◽  
Cardiac Conduction ◽  
Molecular Profile ◽  
Signature Genes ◽  
Pacemaker Function ◽  
Genes Encoding ◽  
Electrical Impulses ◽  
Functional Analyses

Abstract Background: Sinoatrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. The SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although the SAN pacemaker has been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Results: To characterize the molecular profile of the SAR and elucidate the mechanism of pacemaker function, we utilized the zebrafish transgenic line sqet33mi59BEt to isolate cells of the sinoatrial ring (SAR) of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways involved in pacemaker development. We show that, compared to the rest of the heart, the zebrafish SAR overexpresses several mammalian SAN pacemaker signature genes, which include hcn4 as well as those encoding calcium- and potassium-gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases, which suggest the relevance of our transcriptomics resource to studying human heart conditions. Finally, functional analyses of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, uncovered their novel role in heart development and physiology. Conclusion: Our results established conserved aspects between zebrafish and mammalian pacemaker function and revealed novel factors implicated in maintaining cardiac rhythm. The transcriptome data generated in this study represents a unique and valuable resource for the study of pacemaker function and associated heart diseases.

scholarly journals miR-208a in Cardiac Hypertrophy and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Xing-Huai Huang ◽  
Jia-Lu Li ◽  
Xin-Yue Li ◽  
Shu-Xia Wang ◽  
Zhi-Han Jiao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Development ◽  
Regulatory Networks ◽  
Heart Diseases ◽  
Endocrine Function ◽  
Molecular Networks ◽  
Cardiac Conduction ◽  
Whole Body ◽  
Transgenic Expression ◽  
Hypertrophic Growth

Various stresses, including pressure overload and myocardial stretch, can trigger cardiac remodeling and result in heart diseases. The disorders are associated with high risk of morbidity and mortality and are among the major health problems in the world. MicroRNAs, a class of ~22nt-long small non-coding RNAs, have been found to participate in regulating heart development and function. One of them, miR-208a, a cardiac-specific microRNA, plays key role(s) in modulating gene expression in the heart, and is involved in a broad array of processes in cardiac pathogenesis. Genetic deletion or pharmacological inhibition of miR-208a in rodents attenuated stress-induced cardiac hypertrophy and remodeling. Transgenic expression of miR-208a in the heart was sufficient to cause hypertrophic growth of cardiomyocytes. miR-208a is also a key regulator of cardiac conduction system, either deletion or transgenic expression of miR-208a disturbed heart electrophysiology and could induce arrhythmias. In addition, miR-208a appeared to assist in regulating the expression of fast- and slow-twitch myofiber genes in the heart. Notably, this heart-specific miRNA could also modulate the “endocrine” function of cardiac muscle and govern the systemic energy homeostasis in the whole body. Despite of the critical roles, the underlying regulatory networks involving miR-208a are still elusive. Here, we summarize the progress made in understanding the function and mechanisms of this important miRNA in the heart, and propose several topics to be resolved as well as the hypothetical answers. We speculate that miR-208a may play diverse and even opposite roles by being involved in distinct molecular networks depending on the contexts. A deeper understanding of the precise mechanisms of its action under the conditions of cardiac homeostasis and diseases is needed. The clinical implications of miR-208a are also discussed.

Prenatal ethanol exposure impairs the conduction delay at the atrioventricular junction in the looping heart

2021 ◽  
Author(s):  
Shan Ling ◽  
Michael W Jenkins ◽  
Michiko Watanabe ◽  
Stephanie M Ford ◽  
Andrew M Rollins
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Heart Defects ◽  
Ethanol Exposure ◽  
Cardiac Conduction ◽  
Conduction Delay ◽  
Prenatal Ethanol Exposure ◽  
Endocardial Cushions ◽  
Atrioventricular Junction

The etiology of ethanol-related congenital heart defects has been the focus of much study, but most research has concentrated on cellular and molecular mechanisms. We have shown with optical coherence tomography (OCT) that ethanol exposure led to increased retrograde flow and smaller atrioventricular (AV) cushions compared to controls. Since AV cushions play a role in patterning the conduction delay at the atrioventricular junction (AVJ), this study aims to investigate whether ethanol exposure alters the AVJ conduction in early looping hearts and whether this alteration is related to the decreased cushion size. Quail embryos were exposed to a single dose of ethanol at gastrulation, and Hamburger-Hamilton stage 19 - 20 hearts were dissected for imaging. Cardiac conduction was measured using an optical mapping microscope and we imaged the endocardial cushions using OCT. Our results showed that, compared with controls, ethanol-exposed embryos exhibited abnormally fast AVJ conduction and reduced cushion size. However, this increased conduction velocity (CV) did not strictly correlate with decreased cushion volume and thickness. By matching the CV map to the cushion size map, we found that the slowest conduction location was consistently at the atrial side of the AVJ, which had the thinner cushions, not at the thickest cushion location at the ventricular side as expected. Our findings reveal regional differences in the AVJ myocardium even at this early stage in heart development. These findings reveal the early steps leading to the heterogeneity and complexity of conduction at the mature AVJ, a site where arrhythmias can be initiated.

Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 188-195 ◽  
Author(s):  
Marta Muzio ◽  
Benedetta Apollonio ◽  
Cristina Scielzo ◽  
Michela Frenquelli ◽  
Irene Vandoni ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Signaling Pathways ◽  
Lymphocytic Leukemia ◽  
Molecular Signature ◽  
Human Model ◽  
Molecular Profile ◽  
Activated T Cells ◽  
Akt Activation ◽  
Constitutive Activation

Abstract Stimulation through the B-cell antigen receptor (BCR) is believed to be involved in the natural history of chronic lymphocytic leukemia (CLL). Some cases respond to the in vitro cross-linking of surface immunoglobulin (sIg) with effective activation. In contrast, the remaining cases do not respond to such stimulation, thereby resembling B cells anergized after antigen encounter in vivo. However the biochemical differences between the 2 groups are ill defined, and in humans the term B-cell anergy lacks a molecular definition. We examined the expression and activation of key molecules involved in signaling pathways originating from the BCR, and we report that a proportion of CLL patients (a) expresses constitutively phosphorylated extracellular signal-regulated kinase (ERK)1/2 in the absence of AKT activation; (b) displays constitutive phosphorylation of MEK1/2 and increased nuclear factor of activated T cells (NF-AT) transactivation; and (c) is characterized by cellular unresponsiveness to sIg ligation. This molecular profile recapitulates the signaling pattern of anergic murine B cells. Our data indicate that constitutive activation of mitogen activated protein (MAP) kinase signaling pathway along with NF-AT transactivation in the absence of AKT activation may also represent the molecular signature of anergic human B lymphocytes. CLL cases with this signature may be taken as a human model of anergic B cells aberrantly expanded.

scholarly journals ISCA1 Deficiency Induces Iron Metabolism Disorder and Myocardial Oncosis in Rat

2021 ◽  
Author(s):  
Yahao Ling ◽  
Xinlan Yang ◽  
Xu Zhang ◽  
Feifei Guan ◽  
Xiaolong Qi ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Iron Metabolism ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Pathological Process ◽  
Metabolism Disorder ◽  
Abnormal Metabolism ◽  
Validation Experiments

Abstract The effects of multiple mitochondrial dysfunction (MMD) on heart, a highly mitochondria-dependent tissue, is still unclear. This study was the first to verify the effect of ISCA1 gene deficiency, which has been shown to cause multiple mitochondrial dysfunction syndromes type 5 (MMDS5), on cardiac development in vivo, that is cardiomyocytes suffer from energy shortage due to abnormal metabolism of iron ion, which leads to oncosis and eventually HF and body death. Subsequently, we determine a new interacting molecule for ISCA1, six-transmembrane epithelial antigen of prostate 3 (STEAP3), which acts as a reductase in the reduction of Fe3+ to Fe2+. Forward and reverse validation experiments demonstrated that STEAP3 plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching of clinical therapeutic targets.

scholarly journals Epigenetic Regulation of Cardiac Neural Crest Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Shun Yan ◽  
Jin Lu ◽  
Kai Jiao
Keyword(s):  
Neural Crest ◽  
Epigenetic Regulation ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Heart Defects ◽  
Neural Crest Cells ◽  
Abnormal Development ◽  
Cardiac Neural Crest ◽  
Epigenetic Regulators

The cardiac neural crest cells (cNCCs) is a transient, migratory cell population that contribute to the formation of major arteries and the septa and valves of the heart. Abnormal development of cNCCs leads to a spectrum of congenital heart defects that mainly affect the outflow region of the hearts. Signaling molecules and transcription factors are the best studied regulatory events controlling cNCC development. In recent years, however, accumulated evidence supports that epigenetic regulation also plays an important role in cNCC development. Here, we summarize the functions of epigenetic regulators during cNCC development as well as cNCC related cardiovascular defects. These factors include ATP-dependent chromatin remodeling factors, histone modifiers and DNA methylation modulators. In many cases, mutations in the genes encoding these factors are known to cause inborn heart diseases. A better understanding of epigenetic regulators, their activities and their roles during heart development will ultimately contribute to the development of new clinical applications for patients with congenital heart disease.

At the heart of programming: the role of micro-RNAs

2018 ◽  
Vol 9 (6) ◽  
pp. 615-631 ◽  
Author(s):  
B. Siddeek ◽  
C. Mauduit ◽  
C. Yzydorczyk ◽  
M. Benahmed ◽  
U. Simeoni
Keyword(s):  
Heart Development ◽  
Disease Risk ◽  
Heart Diseases ◽  
Underlying Mechanism ◽  
Micro Rna ◽  
Environmental Challenges ◽  
Micro Rnas ◽  
Heart Functions ◽  
Heart Disease Risk

AbstractEpidemiological and experimental observations tend to prove that environment, lifestyle or nutritional challenges influence heart functions together with genetic factors. Furthermore, when occurring during sensitive windows of heart development, these environmental challenges can induce an ‘altered programming’ of heart development and shape the future heart disease risk. In the etiology of heart diseases driven by environmental challenges, epigenetics has been highlighted as an underlying mechanism, constituting a bridge between environment and heart health. In particular, micro-RNAs which are involved in each step of heart development and functions seem to play a crucial role in the unfavorable programming of heart diseases. This review describes the latest advances in micro-RNA research in heart diseases driven by early exposure to challenges and discusses the use of micro-RNAs as potential targets in the reversal of the pathophysiology.

Signaling mediators modulated by cardioprotective interventions in healthy and diabetic myocardium with ischaemia–reperfusion injury

2018 ◽  
Vol 25 (14) ◽  
pp. 1463-1481 ◽  
Author(s):  
Feyzizadeh Saeid ◽  
Javadi Aniseh ◽  
Badalzadeh Reza ◽  
Vafaee S Manouchehr
Keyword(s):  
Heart Disease ◽  
Reperfusion Injury ◽  
Ischaemic Heart Disease ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Heart Diseases ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Diabetic Myocardium ◽  
Patients With Diabetes

Ischaemic heart diseases are one of the major causes of death in the world. In most patients, ischaemic heart disease is coincident with other risk factors such as diabetes. Patients with diabetes are more prone to cardiac ischaemic dysfunctions including ischaemia–reperfusion injury. Ischaemic preconditioning, postconditioning and remote conditionings are reliable interventions to protect the myocardium against ischaemia–reperfusion injuries through activating various signaling pathways and intracellular mediators. Diabetes can disrupt the intracellular signaling cascades involved in these myocardial protections, and studies have revealed that cardioprotective effects of the conditioning interventions are diminished in the diabetic condition. The complex pathophysiology and poor prognosis of ischaemic heart disease among people with diabetes necessitate the investigation of the interaction of diabetes with ischaemia–reperfusion injury and cardioprotective mechanisms. Reducing the outcomes of ischaemia–reperfusion injury using targeted strategies would be particularly helpful in this population. In this study, we review the protective interventional signaling pathways and mediators which are activated by ischaemic conditioning strategies in healthy and diabetic myocardium with ischaemia–reperfusion injury.

Abstract 3857: Structural Heterogeneities are a Substrate for Re-excitation, Reflection, and Arrhythmogenesis in Cardiac Muscle

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
David S Auerbach ◽  
Sergey Mironov ◽  
Jose Jalife
Keyword(s):  
Cardiac Muscle ◽  
Ventricular Myocytes ◽  
Heart Diseases ◽  
Distal Region ◽  
Neonatal Rat ◽  
Excitable Tissue ◽  
Source To Sink ◽  
Replacement Fibrosis ◽  
Electrical Impulses ◽  
Neonatal Rat Ventricular Myocytes

Background: Heart diseases predispose to arrhythmias and sudden cardiac death by mechanisms that are poorly understood. We tested the hypothesis that in fully excitable tissue abrupt geometrical expansions resulting from varying wall thickness, replacement fibrosis, ischemia, or accessory pathways, set the stage for to-and-fro propagation (reflection) of electrical impulses over the same pathway, leading to premature excitation and reentry initiation. Methods: We used patterned monolayers of cultured neonatal rat ventricular myocytes consisting of two wide regions connected by a fully excitable, thin isthmus (0.1, 0.5, 1, & 2 mm wide, 6 mm long). We compared control monolayers with those overexpressing Na channels (NaCh, Ad-hSCN5a). Impulse propagation was optically imaged (Di-8-ANEPPS) at high resolution. Results: Impulses initiated proximally in a wide region propagated 1:1 through relatively broad isthmuses (2 mm) and then into the distal expansion at higher frequencies than through narrower isthmuses (0.1 mm). In control monolayers, with relatively low excitability, the prevalence of reflection was small (15%, n=61). NaCh overexpression increased excitability. It also increased the incidence of reflection (38%, n=26). In homogeneous monolayers, NaCh overexpression increased the conduction velocity (15–17%) and prolonged the action potential duration (APD, 21–26%) at the frequencies (2– 4 Hz) at which reflection occurred. During reflection, the APD at the distal expansion was prolonged, compared to APDs within the isthmus or distally when there was no reflection. APD prolongation provided a substrate for local phase-3 re-excitation at the isthmus, and thus reflection. In some cases, reflection was sustained over several consecutive beats. Reflection also triggered the initiation of reentry; as the beat reflected back, a small distal region was re-excited, resulting in unidirectional propagation and the initiation of reentry. Reflection was never observed in structurally homogeneous monolayers, whether with or without the presence of NaCh overexpression. Conclusion: Source-to-sink mismatch in areas of cardiac muscle expansion creates APD heterogeneities, which may serve as a substrate for reflection and arrhythmogenesis.

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