Review articleNotch signaling and cardiac repair
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.
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2018, European Journal of Cell BiologyCitation Excerpt :The activation of Notch1 is a critical determinant of the transition of adult CSCs to the compartment of amplifying myocytes, and inhibition of this pathway has dramatic negative consequences on the replacement of myocytes and adaptation of the myocardium to ischemic injury (Boni et al., 2008). The importance of Notch is stressed by Notch inhibition during the first week of postnatal life leading to dilated cardiomyopathy in adult mice (Gude and Sussman, 2012). The CSCN is not well defined in terms of location and cellular architecture, but cardiomyocyte-committed cells and interstitial supporting cells are certainly present in the adult heart.
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