The Roles of Neuregulin-1 in Cardiac Development, Homeostasis, and Disease

Rupert, Cassady E.; Coulombe, Kareen L K

doi:10.4137/bmi.s20061

Cited by 57 publications

(58 citation statements)

References 82 publications

(93 reference statements)

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“…The Nrg1-ErbB2/4 signaling pathway has been implicated in many aspects of vertebrate cardiac biology ranging from heart development to homeostasis and disease [5]. Transmembrane pro-Nrg1 is expressed on endocardial and microvascular endothelial cells where it is cleaved by extracellular secretases to release active Nrg1 [6–9].…”

Section: Introductionmentioning

confidence: 99%

“…This ligand and receptor interaction subsequently stimulates hetero-dimerization of ErbB4 with its essential co-receptor ErbB2, leading to activation of ErbB2 tyrosine kinase activity and downstream signaling [10–12]. Recent reports have underscored the importance of the Nrg1-ErbB2/4 signaling pathway in cardiac repair processes, and recombinant Nrg1 is currently in clinical trials as a heart failure therapeutic, but the role of Nrg1 in development is largely unknown [5,13–19]. A refined understanding of this role could provide insight into CHDs or inform the development of improved therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish

et al. 2016

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The Neuregulin-1 (Nrg1) signaling pathway has been widely implicated in many aspects of heart development including cardiac trabeculation. Cardiac trabeculation is an important morphogenetic process where clusters of ventricular cardiomyocytes extrude and expand into the lumen of the ventricular chambers. In mouse, Nrg1 isoforms containing an immunoglobulin-like (IgG) domain are essential for cardiac trabeculation through interaction with heterodimers of the epidermal growth factor-like (EGF-like) receptors ErbB2/ErbB4. Recent reports have underscored the importance of Nrg1 signaling in cardiac homeostasis and disease, however, placental development has precluded refined evaluation of the role of this pathway in mammals. ErbB2 has been shown to have a developmentally conserved role in cardiac trabeculation in zebrafish, a vertebrate model organism with completely external development, but the requirement for Nrg1 has not been examined. We found that among the multiple Nrg1 isoforms, the IgG domain-containing, type I Nrg1 (nrg1-I) is the only isoform detectable in the heart. Then, using CRISPR/Cas9 gene editing, we targeted the IgG domain of Nrg1 to produce novel alleles, nrg1nc28 and nrg1nc29, encoding nrg1-I and nrg1-II truncations. Our results indicated that zebrafish deficient for nrg1-I developed trabeculae in an ErbB2-dependent manner. Further, these mutants survive to reproductive adulthood with no overt cardiovascular defects. We also found that additional EGF-like ligands were expressed in the zebrafish heart during development of trabeculae. Together, these results suggest that Nrg1 is not the primary effector of trabeculation and/or that other EGF-like ligand(s) activates the ErbB2/ErbB4 pathway, either through functioning as the primary ligand or acting in a redundant manner. Overall, our work provides an example of cross-species differences in EGF family member requirements for an evolutionary conserved process.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish

et al. 2016

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“…In the heart, NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium (1). NRG-1 is essential for the development of the cardiovascular system and the maintenance of adult heart function (2,3). Recently, growing evidence indicates that NRG-1 is a positive regulator of angiogenesis (4,5).…”

Section: Introductionmentioning

confidence: 99%

Expression and secretion of neuregulin-1 in cardiac microvascular endothelial cells treated with angiogenic factors

Gui

et al. 2018

Exp Ther Med

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Abstract. Neuregulin-1 (NRG-1) is a positive regulator of angiogenesis, which suggests there may be an association between NRG-1 and angiogenic factors. The aim of the present study was to investigate the effect of treating human cardiac microvascular endothelial cells (HCMECs) with angiogenic factors on NRG-1 expression and secretion. HCMECs were cultured and stimulated with vascular endothelial growth factor (VEGF; 100 ng/ml), angiopoietin (Ang)-1 (100 ng/ml) or Ang-2 (100 ng/ml) under normal or hypoxia/serum deprivation (Hypo/SD) conditions for 24 h. The expression of ErbB receptors and NRG-1 in HCMECs was measured by western blot analysis and the secretion of NRG-1 in HCMECs was determined by ELISA. The results demonstrated that ErbB2, ErbB3 and ErbB4 were expressed in HCMECs and that ErbB2 expression levels were notably higher than those of ErbB3 and ErbB4. Under normal culture conditions the expression and secretion of NRG

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“…U pacijenata sa stabilnom koronarnom bolešću bez ishemije ili srčane insuficijencije, nivo neuregulina-1 obrnuto je povezan sa težinom koronarne arterijske bolesti. Interesantno je da je nivo neuregulina-1 bio viši u pacijenata sa stres indukovanom ishemijom (15). Moguće je da nivo neuregulina u plazmi može biti klinički indikator u bolestima srca i kardiovaskularnog sistema.…”

Section: Uloga Neuregulina Kao Potencijalnog Biomarkeraunclassified

The importance of neuregulin in the development of heart and diseases of the cardiovascular system

Smiljic¹,

Mijović²,

Savic³

2016

Tim Med Glas

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Sažetak:Neregulin-1 pripada epidermalnim faktorima rasta (EGF) koji imaju ulogu u proliferaciji, diferencijacije i očuvanju funkcije epitelnih ćelija dojke, glijalnih ćelija, neurona i miocita. Deluje na parakrini i jukstakrini način preko familije ErbB tirozin kinaza receptora (ErbB2, ErbB3 i ErbB4) koji sadrže ekstracelularna mesta za ligande, transmembranske domene i tirozin kinaza domene. NRG-ErbB signalni put koji je važan u embrionalnom razvoju srca ima svoju ulogu i u adultnom srcu. Neuregulin se uglavnom sintetiše u endokardno endotelnim ćelijama i endotelnim ćelijama miokardnih kapilara. ErbB3 receptori su distribuirani na endotelnim ćelijama, a ErbB2/ErbB4 kompleks na kardiomiocitima. Solubilni NRG-1 izaziva proliferaciju kardiomiocita u embrionu, povećava preživljavanje, utiče na apoptozu kultura kardiomiocita i indukuje hipertrofični rast u neonatalnim i odraslim ventrikularnim kardiomiocitima. Pored uticaja na proliferaciju i diferencijaciju kardiomiocita, NRG-1 tako e promovis e odgovarajuc u diferencijaciju i regrutovanje ćelija provodnog sistema srca od kontraktilnih kardiomiocitima. Endogeni neuregulin može, tako e, uticati na srčanu funkciju delovanjem na nekardiomiocite promovišući angiogenezu. Kardioprotektivni efekat neuregulina-1 preko nekardiomiocita može se ostvariti povećanjem aktivnosti srčanih fibroblasta, gde administracija neuregilina rezultuje u smanjenju veličine ožiljka. Ishemijska oštećenja kardiomiocita i fizičko opterećenje dovode do aktivacije tkivnog neuregulina-1 koji je potentni inducer mobilizacije endotelnih progenitornih ćelija. S obzirom na to da je neuregulin neophodan u razvoju kardiovaskularnog sistema, regulaciji kardioprotektivnih signalnih mehanizama, moguće je da aplikacija rekombinantnih neuregulin izoformi može imati potencijalnu primenu u terapiji pojednih srčanih oboljenja. Me utim, primena rekombinantnog NRG-1 moz e da stimulis e proliferaciju i nesrc anih c elija. Pitanje je i da li c e upotreba neuregulina u kardioprotekciji aktivirati samo za to namenjene receptore jer ako se NRG-1 daje sistemski može da aktivira receptore u drugim tkivima i promoviše neželjene reakcije. Ključne reči: neuregulin, ErbB receptori, srce, kardiovaskularni system. Summary:Neuregulin-1 belongs to the epidermal growth factors (EGF) which have a role in cell proliferation, differentiation and function maintenance of epithelial breast cells, glial cells, neurons and myocytes. It acts in a paracrine and jucstacrine manner through family ErbB tyrosine kinases receptors (ErbB2, ErbB3, and ErbB4) which contain extracellular places for ligands, transmembrane domains and tyrosin kinase domains. NRG-ErbB signaling pathway that is important in embryonic development of the heart also has its role in adult heart. Neuregulin is mainly synthesized in the endocardial endothelial cells and endothelial cells of the myocardial capillaries. ErbB3 receptors are distributed on the endothelial cells and the ErbB2/ErbB4 complex in cardiomyocytes. Soluble NRG-1 induces proliferation of cardiomyocytes i...

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The Roles of Neuregulin-1 in Cardiac Development, Homeostasis, and Disease

Cited by 57 publications

References 82 publications

IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish

IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish

Expression and secretion of neuregulin-1 in cardiac microvascular endothelial cells treated with angiogenic factors

The importance of neuregulin in the development of heart and diseases of the cardiovascular system

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