**1. Introduction**

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104 Calcific Aortic Valve Disease

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Calcific aortic valve disease represents the predominant pathology of tricuspid (trileaflet) and bicuspid aortic valves in developed countries (Ladich et al., 2011). Accounting for approxi‐ mately half of anatomically isolated aortic stenosis and 25 percent of patients with aortic regurgitation (Roberts, 1970), calcific bicuspid aortic valves requiring surgical intervention present at least two decades earlier than the tricuspid counterpart (Ward, 2000). Mechanisms important in cardiac and organ development — notably, the Notch pathway — have emerged as central players recapitulated and reused during the pathogenesis of calcific aortic valve disease, and support also a common etiology for bicuspid aortic valve and aortic valve calcification (Garg et al., 2005) (Table 1). Active engagement of inflammatory, remodeling, neovascularization and osteogenic (Aikawa et al., 2007a; Aikawa et al., 2007b; Miller et al., 2010; Rajamannan et al., 2003) pathways has conceptually replaced 'degeneration' in calcific aortic valve disease pathogenesis and progression (Dweck et al., 2012). Moreover, these pathways invoke similar mechanisms during cardiac morphogenesis. Dysregulated Notch activity has also been reported in vascular inflammation, macrophage activation (Fung et al., 2007), cardiometabolic disorder, and vascular and aortic valve calcification (Fukuda et al., 2012). Preclinical studies suggest that specific blockade of Notch ligand–receptor signaling potently suppresses vascular calcification and calcific aortic valve disease (Fukuda et al., 2012). In this chapter, we review the mechanisms of Notch signaling, aortic valve dysmor‐ phology pertinent to accelerated valve calcification, and discuss the pathways involving Notch that lead to aortic valve calcification and disease.

© 2013 Fung and Aikawa; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Bray, 2006), whereas S3 is executed by γ-secretase, a protease with many substrates (McCarthy et al., 2009; Wakabayashi and De Strooper, 2008). S1 cleavage is carried out by a furin-like convertase occurring posttranslationally in the trans-Golgi apparatus before translocation of the nascent Notch receptor to the cell surface (Bray, 2006; Kopan and Ilagan, 2009). Following S3 cleavage, the Notch intracellular domain is liberated and enters the nucleus to form a transcription activational complex with the transcriptional factor RBP-Jκ, and the transcrip‐ tional coactivator Mastermind to promote target gene transcription (Bray, 2006; Kopan and Ilagan, 2009). Targets indicative of Notch activity include the basic-helix-loop-helix genes of the hairy and enhancer of split (HES) and the hairy-related (HRT or Hey) family (Bray, 2006;

Notch Signaling in Congenital and Acquired Aortic Valve Disease

http://dx.doi.org/10.5772/56533

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Functionality of Notch signaling components is highly context-dependent and conventionally requires cell-to-cell contact to specify cell fate, differentiation, growth, proliferation, survival and apoptosis (Bray, 2006; Fiuza and Arias, 2007; Guruharsha et al., 2012). Interaction between Notch receptor and ligand on adjacent cells results in asymmetric signal transduction, leading to potentially divergent cell fate decision, phenotypic development and growth (Bray, 2006;

**3.1. Notch dysfunction in aortic valve anomalies and other congenital heart diseases**

its formation during cardiac valve and septum development (Camenisch et al., 2010).

Congenital aortic valve anomalies frequently associate with other abnormalities in neighbor‐ ing structures, including the aortic root (e.g. dilatation, aneurysm), aorta (e.g. coarctation of aorta), ventricular outflow tract (e.g. septal defect, transposition of great vessels), and/or coronary arteries (e.g. coronary anomalies) (Perloff, 2003; Ward, 2000). The association of anomalies is due in part to the complexity and critical function of the endocardial cushion, and

The tight regulation of Notch signaling during murine cardiac morphogenesis, particularly of the cardiac outflow tract and semilunar (aortic and pulmonary) valves, have been recently reviewed in detail by de la Pompa and Epstein (de la Pompa and Epstein, 2012). The evolu‐ tionarily conserved nature of Notch across mammalian species is generally recognized to be applicable to human. The highly coordinated action of Notch in progenitor cell proliferation and differentiation is instrumental during development. Earliest signs of cardiac morphogen‐ esis occur with formation of the cardiac crescent by midline fusion of first and second heart fields that feature expression of Notch1, Dll4 and Jagged1 in the primitive endocardium (de la Pompa and Epstein, 2012; del Monte et al., 2007; Duarte et al., 2004). Continuing cell proliferation and development leads to the generation of the heart tube, consisting of an outer myocardial layer, middle cardiac jelly of extracellular matrix, and an inner endocardial endothelium (Camenisch et al., 2010; de la Pompa and Epstein, 2012). Demarcation of boun‐ dary and tissue layers is marked by expression of Jagged1 limited to the myocardial layer, and Dll4, Notch1, Notch2 and Notch4 in the endocardium. The heart tube gradually undergoes a complex morphologic change with a rightward bend, converting the anterior-posterior

Kopan and Ilagan, 2009).

Kopan and Ilagan, 2009).

**3. Congenital aortic valve disease**

**Table 1.** Major components of the Notch1-Hey-BMP2 axis and their actions in cardiac and aortic valve development, and in aortic valve calcification. BMP, bone morphogenetic protein. DLL4, Delta-like 4. JAG1, Jagged1.
