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The Journal of Physiology logoLink to The Journal of Physiology
. 2012 Dec 3;591(Pt 6):1409–1432. doi: 10.1113/jphysiol.2012.235382

Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential

Kristin Dawson 1,3, Mona Aflaki 1,3, Stanley Nattel 1,2,3
PMCID: PMC3607163  PMID: 23207593

Abstract

The Wnt-Frizzled (Fzd) G-protein-coupled receptor system, involving 19 distinct Wnt ligands and 10 Fzd receptors, plays key roles in the development and functioning of many organ systems. There is increasing evidence that Wnt-Fzd signalling is important in regulating cardiac function. Wnt-Fzd signalling primarily involves a canonical pathway, with dishevelled-1-dependent nuclear translocation of β-catenin that derepresses Wnt-sensitive gene transcription, but can also include non-canonical pathways via phospholipase-C/Ca2+ mobilization and dishevelled-protein activation of small GTPases. Wnt-Fzd effects vary with specific ligand/receptor interactions and associated downstream pathways. This paper reviews the biochemistry and physiology of the Wnt-Fzd complex, and presents current knowledge of Wnt signalling in cardiac remodelling processes such as hypertrophy and fibrosis, as well as disease states such as myocardial infarction (MI), heart failure and arrhythmias. Wnt signalling is activated during hypertrophy; inhibiting Wnt signalling by activating glycogen synthase kinase attenuates the hypertrophic response. Wnt signalling has complex and time-dependent actions post-MI, so that either beneficial or harmful effects might result from Wnt-directed interventions. Stem cell biology, a promising area for therapeutic intervention, is highly regulated by Wnt signalling. The Wnt system regulates fibroblast function, and is prominently altered in arrhythmogenic ventricular cardiomyopathy, a familial disease involving excess deposition of fibroadipose tissue. Wnt signalling controls connexin43 expression, thereby contributing to the regulation of cardiac electrical stability and arrhythmia generation. Although much has been learned about Wnt-Fzd signalling in hypertrophy and infarction, its role is poorly understood for a broad range of other heart disorders. Much more needs to be learned for its contributions to be fully appreciated, and to permit more effective exploitation of its enormous potential in therapeutic development.


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Mona Aflaki (left), Kristin Dawson (centre) and Stanley Nattel (right) work in the Research Centre of the Montreal Heart Institute. Their areas of investigation are varied but include cardiac remodelling, electrophysiology and arrhythmogenesis, with a particular focus on the development of innovative therapeutic approaches to heart disease. The present paper relates to their interest in pathological remodelling paradigms and the potential importance of the Wnt-Frizzled system in the evolution of cardiac disorders. They are studying the system in order to better understand heart disease, with the hope of using the insights gained to identify new therapeutic targets.

Historical context and introduction

The first Wnt gene, int-1, was discovered in 1984. Mice infected with the mouse mammary tumour virus (MMTV) were noted to overexpress int-1, a gene close to integration sites for the MMTV sequence, in their tumours (Nusse et al. 1984). The Drosophila melanogaster gene wingless was subsequently found to be a homologue of int-1 (Rijsewijk et al. 1987). The portmanteau term ‘Wnt1’ arose from the combination of int-1 and wingless. A family of Wnt genes with a characteristic coupling pathway (which came to be known as the Wnt pathway) was subsequently identified. The gene family and associated pathway shows high evolutionary conservation among species. Extensive research in Drosophila revealed that Wnt is critically involved in development (Klaus & Birchmeier, 2008). While wnt1 was first identified as an oncogene, it was only in 1993 that mutations in human cancers were linked to Wnt signalling (Ashton-Rickardt et al. 1989; Groden et al. 1991; Rubinfeld et al. 1993). Activating mutations of the canonical Wnt signalling pathway are responsible for 90% of all colon cancer diagnoses (Giles et al. 2003) and disrupted Wnt signalling occurs in other cancers including cervical, lung and mesothelioma (Okino et al. 2003; Uematsu et al. 2003a,b). Over the last decade, a role of Wnt signalling has come to be recognized in cardiac pathophysiology, and is the focus of this review. We begin by describing the Wnt pathway and its signalling components. We then focus on how dysregulation of Wnt signalling results in processes leading to cardiac dysfunction, particularly cardiac hypertrophy and fibrosis, and then discuss the role of the Wnt system in specific cardiac disease conditions: myocardial infarction (MI), heart failure (HF) and arrhythmias.

The Wnt signalling cascade

Wnt signalling involves two principal pathways – the first-described ‘canonical’ (meaning classical or conventional) β-catenin-dependent and the non- canonical (β-catenin-independent) forms. Wnts are often described as either canonical or non-canonical. However, the tissue context of receptors is more important than the receptor per se in determining the signalling pathway. For example, WNT5A, usually considered to be a ‘non-canonical’ ligand, can also activate canonical signalling in certain receptor environments (Mikels & Nusse, 2006).

β-Catenin dependent (Fig. 1)

Figure 1. β-Catenin-mediated canonical signalling.

Figure 1

A, when sFRP inhibits Wnt or Frizzled or Dkk binds LRP5/6, Wnt signalling is suppressed. The destruction complex (composed of Axin, APC, CK1α, GSK-3β and β-catenin) is assembled. CK1α phosphorylates β-catenin at Ser45, which is followed by phosphorylation at Ser33, Ser37 and Thr41 by GSK-3β. The phosphorylation sites are recognized by the E3-ligase BTrCP and β-catenin is ubiquitinated and targeted to proteasomes for degradation. Transcription of Wnt-responsive genes is repressed by HDAC and Groucho binding to TCF/Lef. B, when Wnt binds to the Frizzled receptor, Wnt signalling is activated. Axin and Dvl-1 are recruited to the membrane and free cytosolic β-catenin accumulates. Non-phosphorylated β-catenin translocates into the nucleus, where it binds TCF/Lef (displacing Groucho) and activates transcription. Among the Wnt-responsive genes that are activated, WISP-1 activates Akt. Akt phosphorylates GSK-3β at Ser9, enhancing its inhibition. Abbreviations: APC, adenomatous polyposis coli; BTrCP, β-transducin repeat containing protein; CK1α, casein kinase 1α; CM, cell membrane; GSK-3β, glycogen synthase kinase 3β; Dkk, Dickkopf; Dvl-1; Dishevelled-1; HDAC, histone deacetylase; NP, nuclear pore; sFRP, secreted frizzled related protein; TCF/Lef, T-cell factor/lymphoid enhancer-binding factor; WISP-1, wnt1 inducible signalling pathway protein 1; TBP, TATA-binding protein.

Wnt ligands interact with Frizzled (Fzd) receptors. When Fzd receptors are unoccupied, β-catenin is phosphorylated in a ‘destruction complex’ (Fig. 1A), followed by ubiquitination and degradation by the proteasome (Rao & Kuhl, 2010). The scaffold protein Axin brings together the destruction complex, including the proteins adenomatous polyposis coli (APC), glycogen synthase kinase (GSK)-3β, casein kinase (CK)-1α and β-catenin. CK1α phosphorylates β-catenin at Ser45, which is followed by GSK-3β phosphorylation at Ser33, Ser37 and Thr41 (Giles et al. 2003; Kikuchi et al. 2011; Rao & Kuhl, 2010). Phosphorylated β-catenin is recognized by the E3-ligase β-transducin repeat-containing protein (BTrCP), which ubiquitinates β-catenin and targets it for proteasomal degradation. When nuclear β-catenin is absent, the transcription factor T-cell factor/lymphoid enhancer factor (TCF/Lef) recruits co-repressors (histone deacetylases (HDACs) and Groucho) to inhibit transcription of Wnt-responsive genes (Kikuchi et al. 2011; Rao & Kuhl, 2010).

When Wnt ligands bind Fzd receptors (Fig. 1B) and the co-receptor low-density lipoprotein receptor-related protein (LRP)5/6, the pathway is activated and dishevelled-1 (Dvl-1) is recruited to the membrane (Gao & Chen, 2010; Kikuchi et al. 2011). Axin recruitment to the membrane leads to disassembly of the destruction complex. No longer subject to degradation, β-catenin accumulates in the cytoplasm and translocates into the nucleus. In the nucleus, β-catenin binds to TCF/Lef (displacing Groucho and HDAC), derepressing the transcription factor (Rao & Kuhl, 2010; Kikuchi et al. 2011). Wnt-responsive genes are then activated, including WNT1-inducible signalling-pathway protein 1 (WISP1), cell cycle-related proteins (c-myc, cyclin D) and the negative regulator Axin2. Although the Wnt pathway is ubiquitous and evolutionarily conserved, the specific genes it regulates are cell-type and context dependent (Lam & Gottardi, 2011). WNT1, 3A and 8 typically signal through this pathway (Kikuchi et al. 2011).

β-Catenin independent (Fig. 2)

Figure 2. β-Catenin-independent signalling.

Figure 2

A, the planar cell polarity (PCP) pathway is activated by Fzd receptors independent of LPR5/6. Upon Fzd activation, Dvl-1 transduces the signal through small GTPases. Daam1 forms a complex with Dvl-1, which activates Rho and ROCK. In a second pathway independent of Daam1, activated Dvl-1 stimulates Rac1, which regulates JNK. B, Wnt/Ca2+ pathway. Activation of Fzd receptors recruits heteromeric G-proteins that activate phospholipase C (PLC), producing DAG and IP3. DAG directly activates PKC. IP3 increases intracellular [Ca2+], activating Ca2+-sensitive enzymes such as CaMKII, calcineurin and PKC. Abbreviations: CaMKII, Ca2+/calmodulin-dependent protein kinases II; Daam-1, Dishevelled associated activator of morphogenesis-1; Fzd, Frizzled; JNK, c-Jun terminal kinase; PKC, protein kinase C; PLC, phospholipase C; ROCK, Rho-associated kinase.

Planar cell polarity (PCP) pathway (Fig. 2A)

The PCP pathway (Fig. 2A) was first discovered in a genetic screen in Drosophila (Seifert & Mlodzik, 2007). In vertebrates, this pathway is crucial for gastrulation, sensory cell orientation, cytoskeleton re-organization and directed migration. Non-canonical Wnt signalling is mediated through Fzds but LPR5/6 is not involved (He et al. 2004). Dvl-1 transduces the signal through two small GTPases: Rho and Rac (Wallingford & Habas, 2005; Fig. 2). In the Rho signalling branch, Dvl-1 forms a complex with Daam1 and activates Rho (Habas et al. 2001). Rho-GTPase then activates the Rho-associated kinase (ROCK). In the second branch, Dvl-1 activates Rac and c-Jun N-terminal kinase (JNK), without involving Daam1. The DEP domain of Dvl-1 is crucial for JNK activation (Li et al. 1999). Little is known about Wnt/Fzd signalling downstream to JNK (Li et al. 1999), or how the two pathways interact to regulate biological functions.

Wnt/Ca2+ pathway (Fig. 2B)

Some Wnts (such as WNT5A and WNT11) act through pertussis toxin-sensitive G-proteins, causing Gβγ-dimer dissociation from Gα and activation of phospholipase C (PLC; Slusarski et al. 1997). PLC cleaves phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors, which release Ca2+ from subcellular stores such as the endoplasmic reticulum (ER). The resulting increase in cytosolic Ca2+ activates Ca2+-sensitive proteins such as Ca2+/calmodulin-dependent protein kinase II (CaMKII), calcineurin and protein kinase C (PKC) (Kuhl et al. 2000). Activated calcineurin dephosphorylates the transcription factor nuclear factor of activated T-cells (NFAT), allowing NFAT to translocate into the nucleus where it actives NFAT-responsive genes (Kohn & Moon, 2005). Go/Gi overexpression restores Wnt signalling effects in Fzd-deficient clones (Katanaev et al. 2005).

Biochemistry and physiology

Wnts as ligands

Wnts are highly conserved, hydrophobic, cysteine-rich secreted ligands that control cell proliferation, migration, differentiation, apoptosis and polarity (Blankesteijn et al. 1997; Kwon et al. 2007; Laeremans et al. 2010). Specific timing and location of Wnt activation is necessary for proper development of multiple organs and systems, including the heart (Gessert & Kuhl, 2010). To date, 19 Wnt ligands have been identified (Giles et al. 2003; Gao & Chen, 2010; Kikuchi et al. 2011). Wnts undergo post-translational modification in the ER, including N-linked glycosylation (Smolich et al. 1993; Komekado et al. 2007) and palmitoylation. For example, WNT3A is palmitoylated at Cys77 following glycosylation at Asn87 and Asn298, with both steps needed to secrete active WNT3A (Komekado et al. 2007). Glycosylation and palmitoylation are also required for proper secretion and signalling of WNT5A (Kurayoshi et al. 2007). Secreted Wnts bind to cell membranes and the extracellular matrix (ECM) because of their hydrophobicity. Wnts are also capable of diffusing by binding to lipoproteins (Panakova et al. 2005; Koval et al. 2011) such as low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs) in mammals. Only HDL binding allows release of WNT3A from fibroblasts (Neumann et al. 2009). Heparan sulfate proteoglycans (HSPGs) prevent the aggregation of Wnt ligands, sensitize cells to lower Wnt levels and stabilize the activity of Wnt proteins (Fuerer et al. 2010).

Some non-Wnt ligands can activate Wnt signalling. Examples include Norrie disease protein (NDP) or norrin, and the R-Spondin family (Hendrickx & Leyns, 2008). Whether these non-Wnt ligands are involved in cardiovascular disease is presently unknown. Table 1 lists known Wnts, their effects on different types of cardiac tissues and the evidence for their involvement in cardiovascular disease. Figure 3 summarizes how Wnts differentially affect fibroblast versus cardiomyocyte function.

Table 1.

Wnt ligands and possible cardiac function

Ligand Model Observation Signalling pathway Reference(s)
WNT1 Cardiomyopathic mouse model. Rat neonatal cardiomyocytes β-Catenin enhances Cx43 expression β-Catenin (Ai et al. 2000)
Mouse acute MI Canonical signalling essential for fibroblast function β-Catenin (Duan et al. 2012)
Premature MI in humans Low serum levels independently associated with premature MI N/A (Goliasch et al. 2012)
Mouse ESCs O/E WNT1 Increased ability to generate cardiomyocytes N/A (Weisel et al. 2010)
WNT2 Mouse ESCs Promotes ESC differentiation into cardiomyocytes Non-canonical JNK-AP1 signalling (Onizuka et al. 2012)
ESC cell line Positively regulates cardiomyocyte differentiation N/A (Wang et al. 2007)
Mouse MI ↑ mRNA 11-fold post-MI N/A (Aisagbonhi et al. 2011)
WNT2B Cardiac expression/function unknown
WNT3 Mouse MI Not detected in heart (Barandon et al. 2003)
WNT3A P19CL6 mouse embryonic carcinoma cells Up-regulates early cardiac markers and proportion of differentiated cells β-Catenin (Nakamura et al. 2003)
Immortalized cardiac fibroblasts ↓αSMA, collagen 1, fibronectin mRNA expression with FZD1; increase with FZD2 delay migration β-Catenin (Laeremans et al. 2010)
Mouse, MI Not detected in adult heart N/A (Barandon et al. 2003)
Dog, ventricular tachypacing Not detected in atrial or ventricular fibroblasts N/A (Dawson et al. 2012)
Mouse, fibroblasts ↑ Myofibroblast differentiation, ↑ TGFβ expression β-Catenin (Carthy et al. 2011)
Neonatal rat cardiomyocytes ↑ Aggregation, no effect on proliferation or differentiation β-Catenin (via FZD2) (Toyofuku et al. 2000)
WNT4 Mouse, acute MI ↑ mRNA day 7 and 14 post-MI N/A (Duan et al. 2012)
Mouse, MI ↑ mRNA 18-fold post-MI N/A (Aisagbonhi et al. 2011;
Mouse, MI Not detected in heart N/A Barandon et al. 2003)
WNT5A Immortalized cardiac fibroblasts Delay migration Ca2+ dependent (Laeremans et al. 2010)
Neonatal rat cardiomyocytes ↑ Cardiomyocyte aggregation, no effect on proliferation or differentiation β-Catenin (via FZD2) (Toyofuku et al. 2000)
Neonatal rat cardiomyocytes Promotes cell adhesion in cultured cardiomyocytes JAK/STAT (Fujio et al. 2004)
WNT5B Dog, ventricular tachypacing ↓ mRNA in atrial and ventricular fibroblasts N/A (Dawson et al. 2012)
WNT6 Cardiac expression/function unknown
WNT7A Mouse, acute MI ↑ mRNA day 4 post-MI N/A (Duan et al. 2012)
WNT7B Mouse, MI ↓ To non-detectable levels 7 days post-MI N/A (Barandon et al. 2003)
Congenital heart disease, humans Rare copy number deletion detected in genome-wide search N/A (Soemedi et al. 2012)
WNT8A P19CL6 mouse embryonic carcinoma cells Up-regulates early cardiac markers and proportion of differentiated cells β-Catenin (Nakamura et al. 2003)
Atrial fibrillation, humans Detected in a genome-wide association study N/A (Ellinor et al. 2012)
WNT8B Mouse, MI No detectable expression in normal or MI heart N/A (Aisagbonhi et al. 2011; Barandon et al. 2003)
WNT9A (WNT14) Cardiac expression/function unknown
WNT9B (WNT15) Cardiac expression/function unknown
WNT10A Mouse, MI No detectable expression in heart N/A (Barandon et al. 2003)
WNT10B Human tissue Highest levels in heart and skeletal muscle (Hardiman et al. 1997;
Mouse model of MI ↑ 7 days post-MI Barandon et al. 2003;
Mouse model of MI ↑ mRNA 6-fold post-MI Aisagbonhi et al. 2011)
WNT11 Xenopus laevis. Mouse ESC line (P19) Required for heart formation in Xenopus embryos; treating ESCs results in cardiogenesis PKC and JNK (Pandur et al. 2002)
Zebrafish embryos Generates and maintains ventricular electrical gradient Modulating Ca2+ (Panakova et al. 2010)
Rat MSC hypoxic cardiomyocytes MSCs O/E WNT11 could protect cardiomyocytes from hypoxia if co-cultured post-MI; MSCs O/E WNT11 decreased infarct, improved fractional shortening and increased survival rate N/A (Zuo et al. 2012)
Rat, MI WNT11 O/E in skeletal muscle-derived SCs can induce differentiation down cardiomyocyte lineage Increased JNK signalling
Mouse skeletal muscle-derived SC. Mouse, acute MI Greater survival of WNT11 O/E skeletal muscle-derived SCs and greater differentiation N/A (Xiang et al. 2011)
Mouse, MI ↑ mRNA 3-fold post-MI N/A (Aisagbonhi et al. 2011)
Mouse, MI No detectable expression in heart N/A (Barandon et al. 2003)
WNT11 knock/out mice Cytoskeleton of developing ventricular cardiomyocytes impaired, thinner ventricle, only 20% survival rate at birth N/A (Nagy et al. 2010)
WNT16 Normal human heart tissue Expressed N/A (Fear et al. 2000)
Mouse embryos ↑ In murine model of induced cardiovascular defects N/A (Nath et al. 2009)
Human amniotic fluid ↑ In amniotic fluid of women carrying congenital heart defect fetuses

Abbreviations: Cx43, connexin43; ESCs, embryonic stem cells; MI, myocardial infarction; MSCs, mesenchymal stem cell; N/A, not available; O/E, over-expressing; SCs, stem cell.

Figure 3. Known Wnt effects on fibroblast and cardiomyocyte behaviour.

Figure 3

Cardiomyocytes are depicted on the left side of the figure, with recognized Wnt effects outlined in red boxes. Fibroblasts are depicted on the right side of the figure, with Wnt effects outlined in blue boxes. For references please refer to Table 1, which lists Wnt ligands and how they are involved in cardiac function.

Frizzled receptors

Fzds are seven membrane-spanning domain receptors that constitute the ‘class frizzled’ family of G-protein coupled receptors (GPCRs) (Foord et al. 2005). Sequence analysis has identified 10 Fzd genes (FZD1-10) (Fredriksson et al. 2003). Their extracellular N terminus contains a conserved cysteine-rich domain (CRD) implicated in ligand binding (Dann et al. 2001), whereas the intracellular C-terminal domain is poorly conserved (Wang et al. 1996). A KTXXXW motif in the C-terminal domain provides a protein interaction interface for the receptor that is crucial for β-catenin signalling (Umbhauer et al. 2000). The PDZ domain of mouse Dvl-1 interacts with this motif in vitro (Wong et al. 2003). Different Wnt ligands and Fzd receptors interact to activate canonical and/or non-canonical pathways, as summarized in Table 2.

Table 2.

Potential interactions between Frizzled receptors and Wnt ligands

Frizzled receptor Wnt signalling Wnt ligand Reference(s)
FZD 1 Canonical WNT1 (Tajbakhsh et al. 1998)
WNT2 (Gazit et al. 1999)
WNT3
WNT3A
WNT8 (Liu et al. 1999)
FZD 2 Canonical/non-canonical WNT3A (Toyofuku et al. 2000)
WNT5A (Slusarski et al. 1997; Sheldahl et al. 1999; Toyofuku et al. 2000)
FZD 3 Non-canonical WNT1 (Deardorff et al. 2001)
FZD 4 Canonical/Non-canonical WNT2 (Planutis et al. 2007)
WNT5A (Umbhauer et al. 2000; Chen et al. 2003)
WNT8 (Hsieh et al. 1999)
Norrin (Planutis et al. 2007)
FZD 5 Non-canonical WNT5A (Sen et al. 2001)
WNT7A (Caricasole et al. 2003)
WNT8 (Holmen et al. 2002)
WNT11 (Holmen et al. 2002)
FZD 6 Negative regulator WNT4 (Golan et al. 2004; Lyons et al. 2004)
FZD 7 Canonical/non-canonical WNT5A (Umbhauer et al. 2000)
WNT8B (Medina et al. 2000; Medina & Steinbeisser, 2000)
WNT11 (Kim et al. 2008)
FZD 8 Canonical WNT8 (Deardorff et al. 1998)
FZD 9 WNT2 (Karasawa et al. 2002)
FZD 10 WNT8 (Terasaki et al. 2002)

LDL receptor-related proteins (LRPs)

LRP5 and 6 are Wnt-associated co-receptors in β-catenin-dependent signalling (Tamai et al. 2000). In the absence of Wnt-Fzd interaction, LRP5 and 6 are inactive on the cell surface (Liu et al. 2003). Upon Wnt-Fzd binding, LRPs undergo a conformational change that exposes the LRP cytoplasmic PPSP ([Pro]–Pro–Pro–Ser–Pro) motif (Brennan et al. 2004). The exposed PPSP site is phosphorylated, creating a docking site for axin, which is recruited away from the ‘destruction complex’, preventing β-catenin degradation (Tamai et al. 2000). LRP6 is critical for a variety of Wnt/Fzd pairs such as WNT8/FZD5, WNT11/FZD5 and WNT5A/FZD5 (Holmen et al. 2002).

Endogenous Wnt antagonists

Secreted frizzled-related protein (sFRP). sFRPs are a family of secreted inhibitors, containing five members (sFRP1–5), that inhibit Wnt/Fzd interactions. sFRPs contain a CRD on their N terminus and a Netrin-related motif (NTR) on their C terminus (Lopez-Rios et al. 2008; Esteve & Bovolenta, 2010). sFRPs interact with Fzds via their CRD and bind Wnts through the NTR motif (Lopez-Rios et al. 2008), preventing Wnt-Fzd binding and signalling.

Dickkopf (Dkk)

The Dkk family includes four members, Dkk1–4 (Giles et al. 2003; Kikuchi et al. 2011), which are potent secreted inhibitors of Wnt signalling (Glinka et al. 1998). Dkk1 and 2 bind directly to LRP6 (Mao et al. 2001; Semenov et al. 2001). Together with Kremen 1/2, Dkk binding to LRP6 causes LRP6 internalization, preventing Wnt binding (Mao et al. 2002). Dkk1–3 are expressed in the developing heart (Monaghan et al. 1999; Schneider & Mercola, 2001). Dkk3 is also expressed in adult atrial myocytes, but is absent from ventricles (Krupnik et al. 1999; Monaghan et al. 1999). High Dkk serum levels are associated with premature MI in humans (Goliasch et al. 2012).

Wnt inhibitory factor 1 (WIF-1)

WIF-1 is a secreted antagonist that binds to and inhibits Wnts (Rao & Kuhl, 2010). WIF-1 contains the Wnt inhibitory factor (WIF) Wnt-binding domain, five epidermal growth-factor (EGF)-like domains, a secretion signal and a hydrophilic C terminus (Malinauskas et al. 2011). WIF-1 is known to bind and inhibit WNT3A, 4, 5A, 7A, 9A and 11 (Malinauskas et al. 2011).

Although the role of WIF-1 in cardiovascular disease is unknown, WIF-1 can inhibit connective tissue growth factor (CTGF) (Surmann-Schmitt et al. 2012). CTGF activates fibroblasts and causes hypertrophy in rat cardiomyocytes (Leask, 2010).

Wnt-Fzd signalling in cardiovascular disease: effects on components of cardiac remodelling

Cardiac hypertrophy

Cardiac hypertrophy is characterized by an increase in cell size, and is accompanied by protein synthesis, fibrosis and upregulation of a fetal-gene expression pattern (including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta myosin heavy chain (β-MHC)) (Rohini et al. 2010). Initially an adaptive response, in later stages cardiac hypertrophy can lead to maladaptive remodelling and heart failure. Three forms of hypertrophy are described: eccentric, concentric and physiological. Eccentric hypertrophy, usually due to volume overload, results in cardiac dilation and the elongation of cardiomyocytes. Concentric hypertrophy, typically caused by pressure overload, increases ventricular wall thickness without dilation (Frey et al. 2004). Pathological hypertrophy often involves the action of hypertrophic stimuli such as phenylephrine (PE), angiotensin II and endothelin-1 (ET-1), which activate the calcineurin/NFAT pathway. Physiological hypertrophy occurs in trained athletes and pregnant women. Physiological hypertrophy involves distinct molecular signalling pathways, principally implicating protein kinase B (Akt), which has many targets including GSK-3β.

The progression of cardiac hypertrophy to HF is clearly deleterious. Currently available cardiovascular drugs that have anti-hypertrophic activity inhibit neurohormones, catecholamines (β-blockers) or Ca2+ signalling (Ca2+ channel blockers), or reduce pathological load (vasodilators and diuretics) (McKinsey & Kass, 2007). Cardiac hypertrophy is emerging as an independent target for therapeutic intervention.

Wnt signalling in cardiac hypertrophy

In normal adult cardiomyocytes, Wnt/Fzd signalling is quiescent (Cingolani, 2007). However, the pathway becomes reactivated in disease states, including hypertrophy. Wnt signalling is involved in heart development (Oka et al. 2007) and during hypertrophy an increase in fetal gene expression occurs (Bergmann, 2010). FZD2 receptors are upregulated in pressure-overloaded rat hearts (Blankesteijn et al. 1996). There is a positive correlation between left ventricular mass and FZD2 mRNA levels, and a negative correlation with Dkk-3, in three hypertensive rat models (Cerutti et al. 2006). How individual Wnts effect cardiomyocyte function is outlined in Fig. 3 (left).

Dvl-1 and cardiac hypertrophy

The N-terminal region of Dvl-1, which has 37% homology with the C-terminal region of Axin, is known as the ‘DIX’ domain. The DIX domain allows for Dvl multimerization, producing membrane receptor complexes that amplify signalling by producing a high local concentration of binding sites. The N terminus of Dvl-1 also contains a PDZ domain and a DEP domain (Fig. 4, top). The DEP domain (so-called because it was first identified in Dishevelled, Egl-10 and Pleckstrin proteins) contains about 80 amino acids and is commonly involved in G-protein signalling (Ballon et al. 2006). DIX and PDZ domains contribute to canonical Wnt signalling (Wallingford & Habas, 2005). PDZ and DEP domains are involved in the PCP/Ca2+ (non-canonical) pathway (Veeman et al. 2003). The DEP domain mediates translocation of Dvl-1 to the cell membrane upon Wnt stimulation (Pan et al. 2004).

Figure 4. Role of Dvl-1 and GSK-3β in cardiac hypertrophy.

Figure 4

Top: Dvl-1 is a multimodule protein that is composed of three domains (DIX, PDZ and DEP). Upon Wnt stimulation, DIX and PDZ domains allow formation of the Axin/APC/LRP complex, binding GSK-3β and ck1α and inhibiting their ability to phosphorylate β-catenin. This allows non-phosphorylated β-catenin to displace to the nucleus and effect canonical signalling. Bottom: under resting conditions, GSK-3β is active and suppresses hypertrophy. GSK-3β is inactivated by hypertrophic stimuli, which cause serine-9 phosphorylation, and by Li+. Replacement of serine with alanine prevents inactivation of GSK-3β via PE and ET-1 and reduces the hypertrophic response. Postnatal overexpression of wild-type GSK-3β interferes with normal growth. Abbreviations: AngII, angiotensin-II; DEP, dishevelled, EGL-10, pleckstrin; DIX, dishevelled/axin; ET-1, endothelin-1; GSK-3β, glycogen synthase kinase 3β; PDZ, PSD-95, DLG, ZO1; PE, phenylephrine.

Numerous studies have shown the involvement of Dvl-1 in cardiac hypertrophy (Fig. 4). Pressure overload-induced hypertrophy (transverse aortic constriction, TAC) in rats significantly increases the expression of Dvl-1 (Malekar et al. 2010). Transgenic mice overexpressing Dvl-1 have hypertrophic hearts, reduced ejection fraction and increased mortality (Malekar et al. 2010). Key proteins of the canonical (β-catenin, cyclin D1) and non-canonical (JNK, PKC, CaMKII) pathways are activated in Dvl-1 overexpressing mice. Dvl-1 depleted cardiomyocytes (small interfering RNA) do not develop hypertrophy under isoproterenol treatment (Malekar et al. 2010). In Dvl-1 knockout mice, TAC-induced hypertrophy is attenuated (van de Schans et al. 2007). Increased activity of GSK-3β and increased degradation of β-catenin are also observed.

GSK-3β and cardiac hypertrophy

GSK-3β, a serine/threonine kinase, is catalytically active under resting conditions, repressing β-catenin signalling (Fig. 1A). GSK-3β is inactivated by phosphorylation at serine-9, derepressing β-catenin signalling (Fig. 1B).

GSK-3β is a negative regulator of hypertrophy and is ser-9-phosphorylated by most hypertrophic stimuli (Fig. 4, bottom). β-Adrenoceptor (Morisco et al. 2000), ET-1 and PE (Haq et al. 2000) stimulation inhibit GSK-3β activity. Neonatal cardiomyocytes containing inactivation-resistant GSK-3β (GSK-3β (S9A); Haq et al. 2000) do not respond to PE and ET-1, significantly reducing the hypertrophic response. Inhibition of GSK-3β via LiCl accelerates pressure overload-induced hypertrophy in rats (Tateishi et al. 2010).

Conditional overexpression of constitutively active GSK-3β (S9A-CA) attenuates hypertrophy development and partially reverses pre-existing hypertrophy in a pressure overload model (Sanbe et al. 2003). This mutation also inhibits β-adrenergic-induced hypertrophy and suppresses the hypertrophic response to calcineurin activation (Antos et al. 2002). Thus, GSK-3β activation could prevent pathological hypertrophy. However, GSK-3β overexpression impairs normal cardiac growth and function (Michael et al. 2004). In doubly transgenic mice with constitutively active GSK-3β in a genetic background of hypertrophic cardiomyopathy, hypertrophy is suppressed but cardiac function is impaired and premature death is enhanced (Luckey et al. 2007). The opposite results are seen with cardiac-specific overexpression of dominant negative (DN)-GSK-3β (kinase-dead) in mice (Hirotani et al. 2007). At baseline these mice develop physiological hypertrophy with no fibrosis or apoptosis. After TAC, they show enhanced cardiac mass and function along with inhibition of fibrosis and apoptosis, whereas GSK-3β overexpression induces left ventricular dysfunction and premature death.

Thus, enhanced GSK-3β action has complex consequences, potentially suppressing pathological hypertrophy but also physiological hypertrophy and normal cardiac growth. Differences in timing, duration and specificity of GSK-3β targeting can have major effects on the results (Murphy & Steenbergen, 2005). Novel genetic mouse models that constitutively activate both α- and β-GSK isoforms show normal developmental growth (Matsuda et al. 2008) and reduced pathological hypertrophy in response to β-adrenergic stimulation (Webb et al. 2010).

β-Catenin and cardiac hypertrophy

As both gain and loss of function mutations of β-catenin are embryonically lethal (Grigoryan et al. 2008), conditional mutants are needed to study the role of β-catenin in the adult heart. The stabilization of β-catenin in vitro and in vivo induces hypertrophic growth (Haq et al. 2003) and cardiac-specific deletion of β-catenin attenuates TAC-induced hypertrophy (Qu et al. 2007). In contrast, Baurand et al. (2007) found that β-catenin stabilization abrogates the hypertrophic response to angiotensin II in mice, at the expense of reduced ejection fraction and impaired cardiac function. The discrepancy could be related to different signalling pathways in angiotensin- versus TAC-mediated hypertrophy. In another study, conditional deletion of β-catenin in cardiomyocytes reduced the hypertrophic response to TAC and increased fractional shortening (Chen et al. 2006). The Lef-1 dominant negative mutation showed involvement of the β-catenin-TCF/Lef pathway in normal and pathological hypertrophy (Chen et al. 2006). PE stimulation enhances the recruitment of β-catenin to the ANF promoter region, where it forms a complex with Lef-1 (Zhang et al. 2009). β-Catenin overexpression does not induce ANF, but inhibition of GSK-3β with LiCl directs β-catenin to the ANF promoter (Zhang et al. 2009). In summary, the precise role of β-catenin in cardiac hypertrophy is unclear, and intervening at the level of β-catenin/TCF/Lef may not be practical therapeutically (Blankesteijn et al. 2008).

Non-canonical Wnt signalling in hypertrophy

Mice overexpressing Dvl-1 develop cardiac hypertrophy with activation of both canonical and non-canonical pathways (Malekar et al. 2010). Non-canonical pathways involved in hypertrophy are summarized in Fig. 5. JNK activation increases cell size and ANF expression in cultured cardiomyocytes (Wang et al. 1998). In vivo JNK activation produces a fibrotic/failing heart phenotype (Petrich et al. 2004). Adenoviral-mediated gene transfer of dominant-negative JNK prevents pressure overload hypertrophy in rats (Choukroun et al. 1999). JNK inhibition enhances calcineurin/NFAT signalling (Liang et al. 2003), which is important in pathological hypertrophy (Wilkins et al. 2004). Inhibition of both CaMKII and calcineurin can attenuate cardiac hypertrophy (Diedrichs et al. 2004).

Figure 5. Role of non-canonical (β-catenin-independent) Wnt signalling in hypertrophy.

Figure 5

JNK, calcineurin and CaMKII increase hypertrophy (upward red arrows). Activated calcineurin can dephosphorylate NFAT, which leads to the translocation of NFAT transcription factor to the nucleus. Active GSK-3β can counteract the effect of calcineurin by phosphorylating NFAT. Abbreviations: CaMKII, Ca2+/calmodulin-dependent protein kinases II; GSK-3β, glycogen synthase kinase 3β; JNK, c-Jun terminal kinase; NFAT, nuclear factor of activated T cell.

Potential role in the prevention of cardiac hypertrophy

Suppressing Wnt/Fzd signalling might protect against pathological hypertrophy, but caution is needed because of the role of Wnt/Fzd in normal cardiac growth and other cell functions. Several inhibitors of GSK-3β (Meijer et al. 2004) have been developed. However, both inhibition and over-activation (Mann, 2003) are detrimental. More specific identification of the deregulated Wnts and Fzd receptors in pathological hypertrophy might allow for the definition of more effective and selective targets (Blankesteijn et al. 2008).

Fibrosis

Fibrosis can result from cardiac diseases such as congestive HF or acute MI, but also from cardiac senescence, genetic predisposition and intense exercise (Benito et al. 2011; Rohr, 2012). Fibrosis can impair cardiac relaxation, causing diastolic dysfunction and potentially HF. It also impedes electrical wave propagation, potentially causing arrhythmias.

The Wnt/Fzd pathway is well established to be involved in fibrosis of several organ systems (lung, kidney and liver) (He et al. 2009; Henderson et al. 2010; Akhmetshina et al. 2012). WNT1 and WNT10B are upregulated in pulmonary fibrosis and liver cirrhosis, and canonical Wnt signalling is required for transforming growth factor-β (TGFβ)-mediated fibrosis (Akhmetshina et al. 2012). WNT10B-overexpressing mice show loss of subcutaneous adipose tissue, dermal fibrosis, collagen deposition, myofibroblast accumulation and fibroblast activation (Wei et al. 2011).

Cardiac fibroblasts are regulated in vitro by the Wnt/Fzd pathway (Laeremans et al. 2010). Specific combinations of Wnt ligands and Fzd receptors elicited distinct responses. WNT3A/FZD1 overexpression increased, whereas WNT5A/FZD1 decreased, collagen-I expression. The opposite pattern was seen for FZD2. In vivo, paediatric heart allographs with diastolic dysfunction and severe epicardial fibrosis have nuclear β-catenin accumulation in fibroblasts, suggesting activation of Wntsignalling (Ye et al. 2012). WNT1 is up-regulated in post-MI tissue, and cardiac fibroblasts overexpressing WNT1 show increased proliferation and ECM secretion (Duan et al. 2012). WNT10B is similarly increased post-MI (Barandon et al. 2003; Aisagbonhi et al. 2011). Dkk-1 is decreased in many fibrotic diseases (Akhmetshina et al. 2012), but is increased 4–5 days post-MI (Aisagbonhi et al. 2011; Akhmetshina et al. 2012). In an animal HF model with extensive atrial but little ventricular fibrosis, the largest Wnt-Fzd changes were seen in the atria, with FZD2 showing an over 10-fold increase in atrial fibroblasts (Dawson et al. 2012). A microarray performed on rat cardiac fibroblasts to determine GPCR expression found FZD4 and FZD2 to be the second and fourth most abundant GPCRs, respectively (Snead & Insel, 2012). How different Wnts affect fibroblast function is outlined in Fig. 3 (right).

Wnt-Fzd signalling in cardiovascular disease: cardiac disease states

Myocardial infarction

MI causes tissue necrosis due to a critical mismatch between blood-flow needs and availability (Daskalopoulos et al. 2012). The post-MI period is often divided into an early (<3 days) and a late (>3 days) phase (Sutton & Sharpe, 2000). The early phase involves an inflammatory response with release of chemokines and cytokines that attract inflammatory cells (Daskalopoulos et al. 2012). Following the removal of dead tissue, fibroblasts infiltrate the area and are transformed into myofibroblasts by growth factors such as TGFβ. During the late stage myofibroblasts secrete ECM proteins that form the mature scar. Left ventricular remodelling can proceed for weeks or months after MI (Sutton & Sharpe, 2000; Daskalopoulos et al. 2012). Scarring of the MI zone is essential for normal healing, but with large MIs pathological remodelling causes HF.

Wnt signalling in MI

Wnt signalling is altered in post-MI remodelling (Fig. 6). Wnt-related proteins have been assessed in detail in rats subjected to left anterior descending (LAD) coronary artery ligation (Chen et al. 2004). Dvl-1 is detected in the border zone 24 h post-MI and by day 4 Dvl-1-expression is increased in the border zone and infarct. Dvl-1 expression peaks at 7 days and becomes almost undetectable by day 28. In another study of LAD-ligated rats, gene microarrays were used (LaFramboise et al. 2005). Both WISP1 and APC were upregulated in the infarcted and remote myocardium 1 day post-MI, GSK-3β was upregulated in the remote myocardium and β-catenin was downregulated in the infarct zone. At 28 days post-MI, WISP2 and sFRP4 were upregulated in both the infarct zone and remote myocardium. Another study examined WISP1 expression in post-MI mice, finding increased mRNA levels at 6 h, and 1, 3 and 7 days post-MI with an increase at the protein level at 1, 3 and 7 days (Colston et al. 2007).

Figure 6. Expression changes in Wnt system components post-MI.

Figure 6

Red arrows indicate which direction individual Wnt components change in response to MI, and the time point post-MI when these changes occur are shown next to the arrows.

To better understand Wnt signalling in MI, axin2-LacZ mice were used to study Wnt activation (Oerlemans et al. 2010). Axin2 transcription is induced by β-catenin signalling (Fig. 1); therefore, LacZ-positive cells, marked for axin2 expression, indicate active Wnt signalling post-MI. Healthy adult mice had low-level Wnt signalling. After 7 days LacZ+ cells increased by about 50% and more than doubled by days 14 and 21. LacZ+ cells were found particularly in the border zone but were also increased in the remote area and the infarct area. TOPGAL reporter mice, which express β-galactosidase when TCF/Lef transcription factors in the Wnt pathway are activated by β-catenin signalling, were also examined post-MI (Aisagbonhi et al. 2011). In normal adult mice, Wnt signalling is restricted to endothelial and smooth muscle cells around large vessels and in valve mesenchyme. Beginning 4 days post-MI there was scattered Wnt activation. Seven days post-MI, signalling was mostly in the infarct or peri-infarct area and by 3 weeks post-MI the signalling had disappeared. Wnt activity was observed predominantly in endothelial and α-SMA-expressing mesenchymal cells. Most of the α-SMA-positive cells originated from endothelial cells that had undergone endothelial to mesenchymal transition.

Myofibroblasts show increased expression of the Wnt receptor FZD2 post-MI (Blankesteijn et al. 1997). FZD2 may allow the myofibroblasts to orient spatially to prevent cardiac dilatation.

Modulating Wnt signalling post-MI

Acting on sFRPs. Individual sFRPs show differential regulation post-MI. sFRP1 expression is low in normal mouse tissue but increases in the infarct zone 7 days post-MI, returning to control at 15 days (Barandon et al. 2003). sFRP2 expression increases 4 days post-MI (20- to 30-fold), peaks at day 7 (80- to 100-fold) and is still elevated at 14 days (30- to 40-fold) (Kobayashi et al. 2009). sFRP4 peaks 3–5 days post-MI, is still increased at day 21 and returns to baseline by day 28 (Matsushima et al. 2010).

Different sFRP isoforms contribute differently to post-MI healing. sFRP1 is involved in the inflammatory response. sFRP1 overexpression reduces the prevalence of cardiac rupture from 26.4% to 6.5% in mice (Barandon et al. 2003). Infarct size is reduced in sFRP1 transgenics and the MI scar is thicker. Recently, sFRP1 was overexpressed specifically in bone marrow derived cells (BMCs) engrafted into MI mice to drive expression in leukocytes, and neutrophil infiltration was dramatically decreased in the scar 2–7 days post-MI (Barandon et al. 2011). Scar size was reduced and haemodynamic measures were improved. After MI there were no differences in early mortality (24 h post-surgery), but fatal left ventricular rupture was significantly decreased in the BMC group (10.5%) compared to wildtype littermates (26.3%). When sFRP1 was overexpressed in cardiomyocytes or endothelial cells (with α-MHC and Tie-2 promoters, respectively), neutrophil infiltration, scar formation and frequency of cardiac rupture were unaffected.

sFRP2 is involved in collagen processing. Bmp1/tolloid-like metalloproteinases activate TGFβ and possess procollagen-C proteinases that assist in forming mature collagen fibrils. This process can be inhibited by sFRP2 but not sFRP1 or 3 (He et al. 2010). Injection of sFRP2 into 2-day post-MI infarcts prevented fibrosis 14 days post-MI. Fibrosis prevention occurred without wall thinning or cardiac rupture (He et al. 2010). sFRP2 has a biphasic effect; at low concentrations (10–20 nm) it enhances bmp-1 activity, whereas at higher concentrations (100–200 nm) it has an inhibitory effect (He et al. 2010). In another study, sFRP2-knockout mice had decreased scar collagen 14 days post-MI versus wild-type (15–20%vs. 25–35%) and a higher ejection fraction (40%vs. 15%) (Kobayashi et al. 2009). The discrepancy between these two studies might be due to the biphasic effect of sFRP2. Immediate post-MI sFRP2 levels are high, inhibiting bmp-1 and preventing the deposition of mature collagen. Knocking out sFRP2 would have a deleterious effect at this stage. By 14 days post-MI, sFRP2 expression falls to levels that can enhance collagen deposition, so the delayed administration of sFRP2 might prevent fibrosis.

sFRP4 regulates ECM deposition and cell survival post-MI. Intramuscular sFRP4 injection post-MI prevents impaired cardiac function (Matsushima et al. 2010). β-Catenin signalling and acellular scar formation are reduced.

Modulating β-catenin

Post-MI, epicardial Wnt signalling is enhanced and promotes epithelial–mesenchymal transition into fibroblasts (Duan et al. 2012). Transgenic downregulation of β-catenin signalling substantially impaired cardiac function 8 days after the induction of ischaemia-reperfusion injury. Cardiomyocytes and fibroblasts overexpressing β-catenin exhibit decreased apoptosis, with fibroblasts showing increased cell numbers and cardiomyocytes becoming hypertrophied (Hahn et al. 2006). Adenoviral β-catenin gene transfer into the border zone of MI rats reduced MI size and improved ventricular function, suggesting an important role of canonical Wnt signalling in MI healing.

Small-molecule modulation

An FDA-approved small molecule (pyrvinium) currently on the market to treat pinworms was shown to inhibit Wnt signalling by activating CK1α and thereby promoting β-catenin degradation (Saraswati et al. 2010). This compound was administered into the infarcted zone 10 min post-MI. A marginal but statistically significant improvement in left ventricular diastolic-dimension indices occurred, without changes in systolic dimension or contractile indices. A small peptide inhibitor (UM-206) has been developed that antagonizes WNT3A/WNT5A binding to FZD1 and 2 receptors (Laeremans et al. 2011). UM-206 administration for 5 weeks post-MI decreased infarct expansion and prevented HF.

Regenerative approaches

The Wnt-Fzd system is very important in stem cell biology (Schuijers & Clevers, 2012). Acute MI increases Wnt signalling in mouse haematopoietic stem cells (HPSCs) (Oerlemans et al. 2010). Modulating Wnt signalling strongly affects HPSC differentiation into cardiomyocytes (Lian et al. 2012). Canonical signalling promoted cardiomyocyte differentiation at early phases and suppressed it at more advanced phases; temporal modulation achieved yields of up to 98% functional cardiomyocytes. Intramyocardial injection of WNT3A post-MI limits cardiac progenitor renewal and differentiation into cardiomyocytes, worsening adverse remodelling (Oikonomopoulos et al. 2011). Skeletal muscle-derived stem cells (MDSCs) overexpressing WNT-11 have increased in vivo survival rates and differentiation into cardiomyocytes (Xiang et al. 2011).

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by degrading mRNA or blocking translation. Several miRs regulate the Wnt pathway. MiR-499 overexpression in rat bone marrow-derived mesenchymal stem cells activates Wnt signalling and promotes cardiomyocyte differentiation (Zhang et al. 2012). TGFβ increases pri-miR-145 and suppresses its target disabled-2 (a tumour suppressor protein involved in stem cell differentiation). miR-145 also increases β-catenin signalling in response to TGFβ (Mayorga & Penn, 2012).

Role in ischaemic preconditioning

Ischaemic preconditioning (IPC) is a process by which prior ischaemia followed by reperfusion protects the heart from subsequent prolonged ischaemia (Sanada et al. 2011). Opening of the mitochondrial permeability transition pore allows small molecules and water to traverse mitochondrial membranes, leading to cell death by apoptosis or necrosis. Opening of the mitochondrial ATP-sensitive K+ channel reduces the mitochondrial membrane potential, decreasing mitochondrial Ca2+ uptake during ischaemia (Murphy & Steenbergen, 2008). GSK-3β is a key integration point in IPC, with GSK-3β phosphorylation/inhibition raising the threshold for oxidative stress-induced mitochondrial permeability transition, and thereby protecting the heart (Juhaszova et al. 2004).

Pharmacological inhibition of GSK-3β with Li+ or SB216763 mimics the effect of IPC and reduces infarct size in rats (Tong et al. 2002). The cardioprotective protein kinase B (Akt) phosphorylates GSK-3β and is itself phosphorylated and activated by WNT1 and WISP1 (Fukumoto et al. 2001; Su et al. 2002; Colston et al. 2007). On the other hand, sFRP1 decreases the phosphorylation of both Akt and GSK-3β (Fukumoto et al. 2001; Dufourcq et al. 2002). sFRP1-overexpressing transgenic mice have attenuated phosphorylation of GSK-3β and protein kinase Cɛ activation in response to IPC, enhancing infarct size and impairing cardiac function post-ischaemia (Barandon et al. 2005). Diabetic rat hearts show increased GSK-3β activity and reduced cardioprotection from IPC (Yadav et al. 2010). Pharmacological preconditioning with GSK-3β inhibitors is effective in diabetic hearts (Yadav et al. 2010), highlighting the importance of this pathway. GSK-3β knock-in mice have attenuated IPC (Vigneron et al. 2011). A variety of cardioprotective agents phosphorylate GSK-3β, and their cardioprotective properties are abolished by a GSK-3β-activating (ser9-to-ala) mutation (Juhaszova et al. 2004). GSK-3β knockdown achieves efficient cardioprotection that is not enhanced by GSK-3β phosphorylating cardioprotective interventions. On the other hand, knock-in mice with a mutation preventing GSK-3β phosphorylation continue to demonstrate IPC, indicating that this process may not be essential for preconditioning-induced cardioprotection (Nishino et al. 2008).

Potential role in the management of acute MI

The results of altering Wnt signalling post-MI, described in detail above, are illustrated in Fig. 7. The results are somewhat confusing, because interventions that reduce Wnt signalling (injection/overexpression of sFRP1 and 4; antagonizing Wnt3a/5a binding to Fzd1/2) are generally beneficial, but so is enhancing β-catenin signalling. The discrepancies may relate to intervention timing relative to MI, to specific cell types in which Wnt signalling is altered, to specific forms of signalling (canonical vs. non-canonical) and/or to specific properties of individual types of Fzd receptors and their various Wnt ligands. This complexity suggests that improving the clinical outcome post-MI by acting on Wnt signalling will be challenging.

Figure 7. The results of Wnt signalling interventions in MI.

Figure 7

Red text boxes illustrate how modulating Wnt signalling affects the outcome of MI. Overall, inhibiting Wnt signalling appears to be beneficial; however, one study suggests a beneficial role of enhanced canonical Wnt signalling via β-catenin overexpression post-MI.

Heart failure

HF is the common end-product of many cardiovascular disorders that impair cardiac function (Rouleau, 2011). While presently available drugs can limit pathological remodelling and lower associated morbidity/mortality, HF remains a progressive disease, with a survival rate sometimes lower than that of breast cancer in women or bowel cancer in men (Stewart et al. 2001). Understanding the role of the Wnt-Fzd system in HF might create new opportunities for therapeutic development.

Table 3 contains a summary of studies implicating Wnt signalling in HF. Wnt signalling can influence the progression from hypertrophy to HF, as well as the likelihood of HF development post-MI, as discussed extensively above. Much less is known about the role of Wnt-Fzd in other conditions leading to HF. Cardiac-specific overexpression of Dvl-1 causes extensive hypertrophy, HF and premature death in mice (Malekar et al. 2010). Apoptotic cell death is increased in HF (Kang & Izumo, 2000). Wnt signalling has complex effects on apoptosis, although WNT1 appears to be clearly anti-apoptotic (Pecina-Slaus, 2010), preventing the release of cytochrome C from mitochondria (Chen et al. 2001). The expression of sFRP3 and 4, which antagonize Wnt signalling and have pro-apoptotic properties, increases 2- to 3-fold in the failing human heart (Schumann et al. 2000). GSK-3β activity is depressed in failing human hearts. Akt activation and consequent GSK-3β inhibition protects cells from apoptosis (Haq et al. 2001).

Table 3.

Studies of Wnt signalling involvement in heart failure

Model Wnt signalling components Underlying cause of heart failure Reference(s)
Transgenic mice (Dvl-1 overexpression) ↑ Dvl-1 Hypertrophic remodelling (Malekar et al. 2010)
↑ Canonical signalling/non-canonical ↑ Apoptosis
Human HF ↑ sFRP3, ↑ sFRP4 Dilated cardiomyopathy (Schumann et al. 2000)
↓ Canonical signalling Coronary artery disease
Human HF ↑ AKT Hypertension, coronary artery disease (Haq et al. 2001)
↓ GSK-3β Idiopathic dilated cardiomyopathy
↑ Calcineurin activity
Rat aorto-caval fistula ↑ WISP2 Chronic volume overload (Melenovsky et al. 2011)
Cardiac hypertrophy
Pulmonary congestion
Transgenic mice (RGS-19 overexpression) ↑ Akt Abnormal Wnt signalling (Ji et al. 2010)
Plakoglobin-overexpressing mice ↑ WNT5B Arrhythmogenic right ventricular cardiomyopathy (Lombardi et al. 2009; Lombardi and Marian, 2011)
↓ Canonical signalling
Mice (MI) WNT3A/WNT5A antagonist UM206 improved HF Myocardial infarction (Laeremans et al. 2011)
↑ FZD2
Transgenic mice (SFRP1 overexpression) ↑ SFRP1 improved HF Myocardial infarction (Barandon et al. 2003)
Rat (MI) SFRP2 injection improved HF Myocardial infarction (He et al. 2010)

Chronic volume overload due to aorto-caval fistula (ACF) leads to HF in rats, and causes a 4.5-fold increase in WISP2 (CNN5) expression (Melenovsky et al. 2011). WISP2-overexpressing mice are protected from pressure overload-induced hypertrophy (Yoon et al. 2010). Thus, early increases in WISP2 may act as an adaptive response to volume overload.

Fzds are GPCRs, with the cytoplasmic domains conferring canonical signalling (Liu et al. 2001). Regulator of G-protein signalling (RGS) proteins accelerate GTP hydrolysis by the activated Gα-subunit, suppressing signalling (Hollinger & Hepler, 2002). RGS19 inhibits the Wnt/β-catenin signalling pathway by accelerating breakdown of Gαo (Feigin & Malbon, 2007). RGS19 overexpression produces important abnormalities in cardiac development and premature death in mice (Ji et al. 2010). Mice surviving to adulthood have thinned ventricular walls and increased HF biomarkers such as BNP and β-MHC. RGS-transgenic mice embryos show ventricular wall thinning and ventricular septal defects, similar to β-catenin-deletion mice.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease that classically affects predominantly the right ventricle, but can also prominently affect the left ventricle and present with HF (Deyell et al. 2011). The hallmark feature of ARVC is the replacement of cardiomyocytes by fibroadipose tissue. Right ventricular dilatation, local aneurysms and HF are features of advanced disease (Lombardi & Marian, 2011). Mutations in genes encoding desmosomal proteins such as plakophillin, desmoplakin and plakoglobin (PG) are prominent causes (Gollob et al. 2011). PG (also known as γ-catenin) has 85% sequence identity to β-catenin and competes with β-catenin for nuclear binding to TCF/Lef. Desmoplakin knockdown causes nuclear translocation of PG in an atrial cardiomyocyte-derived cell line (Garcia-Gras et al. 2006), thereby suppressing Wnt signalling and switching the cellular gene expression pattern to an adipogenic/fibrogenic profile. Cardiac-restricted desmoplakin knockout causes embryonic lethality, cardiac dysfunction and fibroadipocyte replacement of cardiomyocytes (Garcia-Gras et al. 2006). Activation of Wnt signalling inhibits adipogenic transcription factors and activates myogenesis (Ross et al. 2000). Transgenic mice overexpressing PG in the myocyte lineage showed increased PG translocation to the nucleus and extensive cardiac adipocyte infiltration (Lombardi et al. 2009). Reduced β-catenin binding to target proteins due to competition with PG was demonstrated, along with reduced expression of Wnt-sensitive genes and increases in adipogenic factors normally suppressed by Wnt signalling (Lombardi et al. 2009). An increase in the expression of WNT5B was also seen; WNT5B inhibits the Wnt pathway and favours adipogenesis (Kanazawa et al. 2005).

Cardiac arrhythmias

Cardiac arrhythmias can result from other forms of heart disease, or occur as primary conditions caused by a variety of genetic and environmental factors. Little is known about the role of the Wnt pathway in arrhythmia generation. As discussed above, Wnt signalling abnormalities contribute to ARVC, which is an important cause of familial sudden death (Gollob et al. 2011). The generation and propagation of cardiac action potentials depends on the proper functioning of a variety of ion channels as well as gap junctions. Connexin43, connexin40 and connexin45 are ion-conducting hemichannels that connect cardiomyocytes at gap junctions, making the heart into a well-coupled electrical syncytium (Dupont et al. 2001). Disrupting connexin expression or phosphorylation can impair electrical communication in gap junctions, resulting in arrhythmia generation and maintenance (Dupont et al. 2001; Burstein et al. 2009; Jansen et al. 2012). Neonatal rat cardiomyocytes treated with the Wnt inhibitor Li+ show increased connexin43 expression and enhanced coupling (Ai et al. 2000). In a mouse model of cardiomyopathy due to diphtheria toxin overexpression, connexin43 and β-catenin expression are reduced, and Wnt signalling leads to enhanced β-catenin/connexin43 colocalization (Ai et al. 2000). Wnt signalling thus regulates connexin43 expression and disturbed Wnt signalling could lead to arrhythmia generation in diseased hearts. Interestingly, WNT8A was associated with atrial fibrillation in a recent genome-wide association study (Ellinor et al. 2012).

Wnt signalling in cardiac development

The Wnt signalling system plays a vital and diverse role in cardiac differentiation and development. Depending on the timing of onset of Wnt signalling it can have different effects on development: suppression or activation. The final outcome depends on many factors, including the properties of cardiac progenitor cell populations, the time that Wnt signalling is activated during development and the type of Wnt ligand involved. The role of Wnt signalling in development has been the subject of a vast array of research that is beyond the scope of this review; we refer the interested reader to relevant detailed review papers (Brade et al. 2006; Gessert & Kuhl, 2010). Many of the effects of altered Wnt signalling in the fully developed heart derive from the modulation of pathways that are important in development, as detailed in many sections of this paper.

Conclusions

Wnt signalling is important in cardiac development and a variety of cardiac pathologies. Because Wnt signalling involves a plethora of potential ligands, receptors, inhibitors and second messengers, the system is very complex and its effects may be quite varied according to the cell system, specific ligands/receptors involved and timing of any interventions. This complexity presents a challenge to investigators, but at the same time offers rich possibilities for new insights into cardiac pathophysiology and the identification of new therapeutic targets.

Acknowledgments

The authors thank France Theriault for expert secretarial assistance, as well as the Canadian Institutes for Health Research (6957, 44365, 68929), the Quebec Heart and Stroke Foundation and the Fondation Leducq for research funding.

Glossary

ANF

atrial natriuretic factor

APC

adenomatous polyposis coli

BMC

bone marrow derived cell

CaMKII

Ca2+/calmodulin-dependent protein kinase II

CK

casein kinase

CRD

cysteine-rich domain

DAG

diacylglycerol

Dvl

dishevelled

ECM

extracellular matrix

ER

endoplasmic reticulum

Et-1

endothelin-1

GPCRs

G-protein coupled receptors

GSK

glycogen synthase kinase

HDL

high-density lipoprotein

HF

heart failure

HPSC

haematopoietic stem cell

IP3

inositol-1,4,5-trisphosphate

IPC

ischaemic preconditioning

JNK

c-Jun N-terminal kinase

LAD

left anterior descending

LDL

low-density lipoprotein

Lef

lymphoid enhancer factor

LRP

lipoprotein receptor-related protein

MHC

myosin heavy chain

MI

myocardial infarction

NFAT

nuclear factor of activated T-cells

NTR

Netrin-related

PCP

planar cell polarity

PE

phenylephrine

PG

plakoglobin

PLC

phospholipase C

RGS

Regulator of G-protein signalling

ROCK

Rho-associated kinase

sFRP

secreted frizzled-related protein

TAC

transverse aortic constriction

TCF

T-cell factor

TGFβ

transforming growth factor-β

WIF

Wnt inhibitory factor

WISP

WNT1-inducible signalling-pathway protein

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