Review article
Notch signaling and cardiac repair

https://doi.org/10.1016/j.yjmcc.2012.03.007Get rights and content

Abstract

Notch signaling is critical for proper heart development and recently has been reported to participate in adult cardiac repair. Notch resides at the cell surface as a single pass transmembrane receptor, transits through the cytoplasm following activation, and acts as a transcription factor upon entering the nucleus. This dynamic and widespread cellular distribution allows for potential interactions with many signaling and binding partners. Notch displays temporal as well as spatial versatility, acting as a strong developmental signal, controlling cell fate determination and lineage commitment, and playing a pivotal role in embryonic and adult stem cell proliferation and differentiation. This review serves as an update of recent literature addressing Notch signaling in the heart, with attention to findings from noncardiac research that provide clues for further interpretation of how the Notch pathway influences cardiac biology. Specific areas of focus include Notch signaling in adult myocardium following pathologic injury, the role of Notch in cardiac progenitor cells with respect to differentiation and cardiac repair, crosstalk between Notch and other cardiac signaling pathways, and emerging aspects of noncanonical Notch signaling in heart.

Highlights

► Activation of Notch promotes myocardial repair. ► Notch signaling controls cardiac progenitor specification and differentiation. ► Notch crosstalks with survival pathways in heart. ► Noncanonical Notch signaling may participate in cardiac repair.

Introduction

Nearly one hundred years after the first description of Notch in fruit flies, scientific publications abound examining this deceptively simple pathway in almost every aspect of eukaryotic biology [1], [2], [3], [4], [5], [6], [7], [8], [9]. The mammalian Notch family includes four receptors (Notch1–4) and five canonical ligands (Jagged1, Jagged2 Delta1, Delta3, Delta4). Receptors and ligands share similar overall structure: a large extracellular domain, single pass transmembrane region, and an intracellular domain. Binding of the ligand and receptor extracellular domains on adjacent cells triggers receptor activation through two proteolytic cleavage events: ADAM/TACE catalyzes release of the extracellular ligand-bound region of the receptor, and presenilin, the active component of the gamma secretase complex, cleaves the transmembrane region. The untethered intracellular domain then enters the nucleus and binds CBF1/Su(H)/Lag-1 (CSL) transcription factor, displacing co-repressors and activating expression of downstream target genes, the best known of which are the Hes and Hes-related (Hesr) family of bHLH transcriptional repressor proteins. The Notch pathway participates in multiple cellular functions during development and adulthood, including cell–cell communication, maintaining tissue boundaries, cell fate determination, differentiation, tissue homeostasis and regeneration.

During cardiac development all Notch receptors and ligands participate in patterning and formation of the cardiac layers, as illustrated and described in great detail by de la Pompa and Epstein in their recent review of Notch signaling in cardiac development and disease [10]. All mammalian Notch receptors and four ligands (excluding Delta3, which exhibits atypical signaling properties) have likewise been measured by quantitative PCR and immunohistochemistry in adult rat myocardium and failing human heart tissue, with Notch3 and 4 identified as the predominant receptors in isolated adult rat cardiomyocytes [11]. Jagged1 is expressed in adult mouse myocytes, intracellular Notch1 appears in developing and pathologically challenged adult mouse cardiomyocytes, while Delta4 ligand is detected in nonmyocyte mouse heart cells [12], [13], [14], [15]. Furthermore, Notch1 receptor is expressed in cardiac stem cells located in cardiac niches. Pharmacological ablation of Notch activity by gamma secretase inhibitors during the first week of postnatal life in mice leads to dilated cardiomyopathy in the adult heart, underscoring the importance of Notch1 during cardiomyogenesis [14].

Notch is critical for proper myocardial and outflow tract development. Recent evidence demonstrates that Notch and Jagged1 signal to each other in developing cardiac vasculature to create layers of smooth muscle around endothelium [16], [17]. Mutations in Notch receptors and ligands can perturb proper development and formation of the heart. Diseases impacting adult heart function arising from Notch receptor or ligand mutations include Alagille syndrome (Jagged1 [18], [19], Notch2 [20], CADASIL (Notch3, [21]) and aortic valve disorder (Notch1, [22], [23]). Several excellent reviews summarize the role of Notch in cardiac development and disease, and vasculogenesis following injury [24], [25], [26], [27], [28], [29], [30], [31]. Activation of the Notch pathway in damaged adult myocardium has been linked to survival, proliferative and regenerative signaling [11], [12], [13], [15], [32], [33]. Collectively these studies indicate Notch as a potent formative and reparative signal in the mammalian heart.

Section snippets

Models of cardiac Notch activation and inhibition

Genetic and pharmacological models of Notch pathway activation or inhibition have revealed various roles for Notch in the developing and adult heart. Cardiomyocyte specific overexpression of the Notch intracellular domain (NICD) or silencing of Notch in embryonic cardiomyocytes both result in atrial and ventricular septal defects [32], [34], [35]. In adult heart, however, conditional activation of Notch is cardioprotective, while Notch blockade exacerbates damage following infarction [14], [32]

Notch in cardiac myocytes

Several recent studies have examined Notch expression and signaling in cardiomyocytes with respect to proliferation and survival [12], [13], [15], [32], [33]. Notch pathway activation has been documented in adult mammalian heart following infarction and hypertrophy [11], [12], [32], [38]. Overexpression of activated Notch in infarcted myocardium, whether through genetic engineering or transient overexpression, abrogates damage and promotes proliferative signaling in cardiac myocytes, whereas

Notch in progenitors

Notch signaling during cardiac development is an ongoing focus of scientific investigation [23], [25], [26], [27], [28], [29], [40], [41], [42], [43], [44], [45], [46]. With the advent of cell-based therapy for the treatment of cardiac disease [47], [48], the role of Notch in cardiac lineage commitment in diverse stem and progenitor cell types has generated great interest [36]. Timing, dose and cellular context are crucial to the outcome of Notch signaling [49], [50], [51], [52] during

Notch signaling and crosstalk

Notch crosstalk with other cellular signaling pathways has been extensively characterized in the context of cancer and development and to some extent in vascular, stem cell and cardiac systems [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93]. Zhang et al. propose an elaborate signaling network in confluent endothelial cells whereby Angiopoietin-1/Tie-2 induction of PI3K/Akt inhibits GSK3B and stabilizes B-catenin, which forms a complex with NICD/RBPJk to

Noncanonical Notch

In canonical Notch signaling, DSL (Delta, Serrate, LAG-2 family) ligand activation of the Notch receptor on a neighboring cell triggers proteolytic cleavage and subsequent translocation of the receptor intracellular domain to the nucleus, where binding to the canonical CSL target converts it from a transcriptional repressor to an activator of Notch target genes. Exceptions to this “rule” surface with increasing frequency in the scientific literature as novel modes of Notch interaction are

Conclusions

In conclusion, in addition to its previously well established role in cardiac development and disease, the Notch pathway is emerging as an important and complex signaling cascade in adult heart. Key outstanding questions regarding Notch signaling in cardiac repair are multiple and include 1) How does Notch signaling participate in cardiac repair in resident cardiac cell types (myocytes, vasculature, cardiac fibroblasts, stem cells) and in stem cells recruited from the circulation following

Disclosure statement

None.

Acknowledgements

Many thanks to the Sussman lab and in particular Eri Joyo for their help and support. M.A.S. was supported by National Heart, Lung, and Blood Institute Grants R21HL102714, R01HL067245, R37HL091102, P01HL085577, RC1HL100891, R21HL102613, R21HL102714, R21HL104544 and R01HL105759. N.A.G. was supported by NHLBI Grant R21HL104544.

References (142)

  • J.M. Butler et al.

    Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells

    Cell Stem Cell

    (2010 Mar 5)
  • I.M. Conboy et al.

    The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis

    Dev Cell

    (2002 Sep)
  • D. Luo et al.

    The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis

    Semin Cell Dev Biol

    (2005 Aug-Oct)
  • S. Guo et al.

    Role of Notch and its oncogenic signaling crosstalk in breast cancer

    Biochim Biophys Acta

    (2011 Apr)
  • U. Koch et al.

    Notch in T-ALL: new players in a complex disease

    Trends Immunol

    (2011 Sep)
  • C.S. Moreno

    The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways

    Am J Pathol

    (2010 Feb)
  • J. Zhang et al.

    Angiopoietin-1/Tie2 signal augments basal Notch signal controlling vascular quiescence by inducing delta-like 4 expression through AKT-mediated activation of beta-catenin

    J Biol Chem

    (2011 Mar 11)
  • A.C. Chang et al.

    Notch Initiates the Endothelial-to-Mesenchymal Transition in the Atrioventricular Canal through Autocrine Activation of Soluble Guanylyl Cyclase

    Dev Cell

    (2011 Aug 16)
  • M.G. Cornejo et al.

    Lo Celso C, Lopez CK, et al

    Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification. Blood

    (2011 Aug 4)
  • L.S. Campos et al.

    Notch, epidermal growth factor receptor, and beta1-integrin pathways are coordinated in neural stem cells

    J Biol Chem

    (2006 Feb 24)
  • S. Artavanis-Tsakonas et al.

    Notch signaling

    Science

    (1995 Apr 14)
  • S.J. Bray

    Notch signalling: a simple pathway becomes complex

    Nat Rev Mol Cell Biol

    (2006 Sep)
  • I. Greenwald

    LIN-12/Notch signaling in C. elegans

  • E.C. Lai

    Notch signaling: control of cell communication and cell fate

    Development

    (2004 Mar)
  • E.R. Andersson et al.

    Notch signaling: simplicity in design, versatility in function

    Development

    (2011 Sep)
  • T. Borggrefe et al.

    Fine-tuning of the intracellular canonical Notch signaling pathway

    Cell Cycle

    (2012 Jan 15)
  • E. Oie et al.

    Activation of Notch signaling in cardiomyocytes during post-infarction remodeling

    Scand Cardiovasc J

    (2010 Dec)
  • N.A. Gude et al.

    Activation of Notch-mediated protective signaling in the myocardium

    Circ Res

    (2008 May 9)
  • A. Croquelois et al.

    Control of the adaptive response of the heart to stress via the Notch1 receptor pathway

    J Exp Med

    (2008 Dec 22)
  • K. Urbanek et al.

    Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart

    Circ Res

    (2010 Aug 6)
  • V.M. Campa et al.

    Notch activates cell cycle reentry and progression in quiescent cardiomyocytes

    J Cell Biol

    (2008 Oct 6)
  • L.J. Manderfield et al.

    Notch Activation of Jagged1 Contributes to the Assembly of the Arterial Wall

    Circulation

    (2011 Dec 6)
  • V.J. Hoglund et al.

    Patterning the Artery Wall by Lateral Induction of Notch Signaling

    Circulation

    (2011 Dec 6)
  • T. Oda et al.

    Mutations in the human Jagged1 gene are responsible for Alagille syndrome

    Nat Genet

    (1997 Jul)
  • L. Li et al.

    Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1

    Nat Genet

    (1997 Jul)
  • Samejima H, Torii C, Kosaki R, Kurosawa K, Yoshihashi H, Muroya K, et al. Screening for Alagille syndrome mutations in...
  • A. Joutel et al.

    Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia

    Nature

    (1996 Oct 24)
  • V. Garg et al.

    Mutations in NOTCH1 cause aortic valve disease

    Nature

    (2005 Sep 8)
  • V. Garg

    Molecular genetics of aortic valve disease

    Curr Opin Cardiol

    (2006 May)
  • R. Jain et al.

    Notch and cardiac outflow tract development

    Ann N Y Acad Sci

    (2010 Feb)
  • F.A. High et al.

    The multifaceted role of Notch in cardiac development and disease

    Nat Rev Genet

    (2008 Jan)
  • J.L. de la Pompa

    Notch signaling in cardiac development and disease

    Pediatr Cardiol

    (2009 Jul)
  • Al Haj Zen A, Madeddu P. Notch signalling in ischaemia-induced angiogenesis. Biochem Soc Trans 2009 Dec; 37(Pt 6):...
  • D. MacGrogan et al.

    Notch signaling in cardiac valve development and disease

    Birth Defects Res A Clin Mol Teratol

    (2011 Jun)
  • P. Kratsios et al.

    Distinct roles for cell-autonomous Notch signaling in cardiomyocytes of the embryonic and adult heart

    Circ Res

    (2010 Feb 19)
  • C. Collesi et al.

    Notch1 signaling stimulates proliferation of immature cardiomyocytes

    J Cell Biol

    (2008 Oct 6)
  • Y. Watanabe et al.

    Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse

    Development

    (2006 May)
  • L. Luna-Zurita et al.

    Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation

    J Clin Invest

    (2010 Oct 1)
  • A. Boni et al.

    Notch1 regulates the fate of cardiac progenitor cells

    Proc Natl Acad Sci U S A

    (2008 Oct 7)
  • T. Grieskamp et al.

    Notch signaling regulates smooth muscle differentiation of epicardium-derived cells

    Circ Res

    (2011 Apr 1)
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