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

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/Ca 2+ 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.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.K. Dawson and M. Aflaki contributed equally to this work and share 1st authorship.

Cilia and coordination of signaling networks during heart development

“…PCP, to promote cell migration and convergent extension movements. 2,189,192,193,196 The link between Wnt signaling and the primary cilium is highly controversial. 32,35,197 However, many Wnt signaling components, such as Fz3, Dvl, and β-catenin, localize to the ciliary/centrosomal axis, and dysregulated Wnt signaling has been reported in cells and tissues with disrupted ciliogenesis or basal body integrity.…”

“…82,[189][190][191][192][193][194] The Wnt signaling network consists of a highly complex signaling arrangement that traditionally is divided into canonical and non-canonical Wnt signaling. 195 In canonical signaling, the binding of Wnt-ligands to Frizzled (Fz) receptors facilitates stabilization of β-catenin, which mediates transcription of canonical Wnt target genes in cell proliferation and differentiation.…”

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

“…Considering that Wnt signaling is reactivated after cardiac injury and its involvement in cardiac fibrosis and hypertrophy (45,46), modulation of Wnt signaling represents a beneficial target to intervene in cardiac diseases. Consistently, inhibition of reactivated Wnt signaling has been shown to attenuate the hypertrophic responses (12)(13)(14).…”

Heart Failure as an Aging-Related Phenotype

“…[22][23][24][25] In spite of such a context-dependency, Wnt/β-catenin signaling is thought to play a pivotal role in the progression of cardiac dysfunction/heart failure. 26) In the canonical Wnt/β-catenin pathway, DKK1 (Dickkopf1) basically inhibits the formation of a ternary complex consisting of LRP5/6, Frizzled, and the Wnt ligand followed by inhibition of the canonical Wnt/β-catenin pathway. DKK1 itself is a target gene of Wnt/β-catenin signaling, thereby establishing a negative feedback loop.…”