Notch-independent RBPJ controls angiogenesis in the adult heart

Trelles, Ramón Dı́az; Scimia, Maria Cecilia; Bushway, Paul J.; Tran, Danh; Monosov, Anna Z.; Monosov, Edward; Peterson, Kirk L.; Rentschler, Stacey; Cabrales, Pedro; Ruiz‐Lozano, Pilar; Mercola, Mark

doi:10.1038/ncomms12088

Cited by 47 publications

(45 citation statements)

References 47 publications

(61 reference statements)

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“…A previous report in which Rbpj was inactivated in the myocardium using the αMhc-Cre driver (49) showed that myocardial RBPJ represses hypoxia-inducible factors (HIFs) to negatively regulate Vegfa expression in a NOTCH-independent manner (50). In situ hybridization of Vegfa in E16.5 Rbpj flox ;cTnT-Cre embryos showed a small but significant increase of Vegfa transcription in the ventricular wall of mutant embryos (Fig 3k-l, o), supporting previous observations (50). VEGFA positively regulates the formation of blood vessels in the ventricles (51).…”

Section: Resultsmentioning

confidence: 99%

MyocardialNotch-Rbpjdeletion does not affect heart development or function

Salguero-Jiménez

Grego-Bessa

D’Amato

et al. 2018

Preprint

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23 24 25 2 26 Abstract 27 During vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk 28 between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation.29 This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of 30 the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown 31 to be crucial for heart development, its physiological role in the myocardium has not been clearly established.32 Here we have used a genetic strategy to evaluate the role of NOTCH in myocardial development. We have 33 inactivated the unique and ubiquitous NOTCH effector RBPJ in the early cardiomyocytes progenitors, and 34 examined its consequences in cardiac development and function. Our results demonstrate that mice with cTnT-35 Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing 36 normal expression of cardiac development markers, and normal adult heart function. Similar observations have 37 been obtained after Notch1 deletion with cTnT-Cre. We have also deleted Rbpj in both myocardial and endocardial 38 progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right 39 ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of 40 cardiac valves territories. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect 41 heart development or adult cardiac function.42 43 44 3 45 Introduction 46 47 The heart is the first organ to form and function during vertebrate development. At embryonic day 7.0 (E7.0) in48 the mouse, cardiac progenitor cells, migrating from the primitive streak, reach the head folds on either side of the 49 midline (1) and by E8.0, fuse and form the primitive heart tube (2). The heart tube consists internally of the 50 endocardium, that is separated from the primitive myocardium by an extracellular matrix termed cardiac jelly (3). 51The NOTCH signaling pathway is crucial for the endocardial-myocardial interactions that regulate the patterning, 52 growth and differentiation of chamber and non-chamber tissues that will develop from E8.5 onwards (4-8). The 53 main components of the pathway are the single-pass transmembrane NOTCH receptors (NOTCH1-4 in mammals) 54 that interact with membrane-bound ligands of the JAGGED (JAG1 and JAG2) and DELTA families (DELTA 55 LIKE1, 3 and 4), expressed in neighboring cells (9, 10). Ligand-receptor interactions leads to three consecutive 56 cleavage events that generate the NOTCH intracellular domain (NICD), which can translocate to the nucleus of 57 the signaling-receiving cell (11). In the nucleus, NICD binds directly to the DNA-binding protein CSL 58 (CBF1/RBPJ/Su(H)/Lag1) (12) and recruits the co-activator Mastermind-like (13, 14). In the absence of N1ICD, 59 ubiquitously expressed RBPJ (recombination signal bi...

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Section: Resultsmentioning

confidence: 99%

MyocardialNotch-Rbpjdeletion does not affect heart development or function

Salguero-Jiménez

Grego-Bessa

D’Amato

et al. 2018

Preprint

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“…Notch signaling is transiently activated during the response to injuries such as myocardial infarction with pressure overload 11, 12, 29 . To determine the persistence of the consequent Notch-induced electrical changes, we fed iNICD mice doxycycline chow for 3 weeks to activate Notch, followed by an 8-week washout period.…”

Section: Resultsmentioning

confidence: 99%

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice

Qiao

Lipovsky

Hicks

et al. 2017

Circulation Research

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Rationale Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes. Objective To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility. Methods and Results To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (iNICD). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including Nkx2-5, Tbx3 and Tbx5 are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including Scn5a (Nav1.5) and Gja5 (connexin 40), are persistently down-regulated long after a transient Notch pulse. Consistent with the reduction in Scn5a transcript, Notch induces global changes in the atrial action potential, including a reduced dVm/dtmax. In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology, and predisposes to an arrhythmogenic substrate. Conclusions Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes resulting in sinus bradycardia, sinus pauses and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome.

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“…Notch is normally quiescent in adult cardiac myocytes, however, a number of recent studies have suggested that Notch signaling is transiently activated in the setting of cardiac injuries, including myocardial infarction, in mouse and zebrafish models 19, 39, 45, 46 . In response to myocardial infarction, Notch induction occurs primarily in border zone cardiac myocytes 39 .…”

Section: Resultsmentioning

confidence: 99%

“…NICD translocates to the nucleus where it forms a complex with its main effector molecule, the DNA-binding transcription factor RBP-J (recombination signal binding protein for immunoglobulin kappa J region, also known as CSL). In the non-activated state, RBP-J bound to target gene promoters can be associated with repressor proteins, such as histone deacetylases and SHARP (SMRT and HDAC associated repressor protein), where it acts in a Notch-independent manner to inhibit target gene activation 18, 19 . Binding of NICD to RBP-J can lead to displacement of corepressors and transform the complex into an activating complex 20 .…”

Section: Introductionmentioning

confidence: 99%

Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents

Khandekar

Springer

Wang

et al. 2016

Circulation Research

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Rationale Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an “induced Purkinje-like” state characterized by prolonged action potential duration and expression of Purkinje enriched genes. Objective To understand the mechanism by which canonical Notch signaling causes action potential prolongation. Methods and Results We find that endogenous Purkinje cells have reduced peak K+ current, Ito and IK,slow when compared with ventricular myocytes. Consistent with partial reprogramming toward a Purkinje-like phenotype, Notch activation decreases peak outward K+ current density, as well as the outward K+ current components Ito,f and IK,slow. Gene expression studies in Notch-activated ventricles demonstrate upregulation of Purkinje-enriched genes Contactin-2 and Scn5a, as well as downregulation of K+ channel subunit genes that contribute to Ito,f and IK,slow. In contrast, inactivation of Notch signaling results in increased cell size commensurate with increased K+ current amplitudes and mimics physiologic hypertrophy. Notch-induced changes in K+ current density are regulated at least in part via transcriptional changes. Chromatin immunoprecipitation demonstrates dynamic RBP-J binding and loss of active histone marks on K+ channel subunit promoters with Notch activation, and similar transcriptional and epigenetic changes occur in a heart failure model. Interestingly, there is a differential response in Notch target gene expression and cellular electrophysiology in left versus right ventricular cardiac myocytes. Conclusions In summary, these findings demonstrate a novel mechanism for regulation of voltage-gated potassium currents in the setting of cardiac pathology, and may provide a novel target for arrhythmia drug design.

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Notch-independent RBPJ controls angiogenesis in the adult heart

Cited by 47 publications

References 47 publications

MyocardialNotch-Rbpjdeletion does not affect heart development or function

MyocardialNotch-Rbpjdeletion does not affect heart development or function

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice

Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents

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