Interventions in Wnt signaling as a novel therapeutic approach to improve myocardial infarct healing

Abstract

Following myocardial infarction, wound healing takes place in the infarct area where the non-viable cardiac tissue is replaced by a scar. Inadequate wound healing or insufficient maintenance of the extracellular matrix in the scar can lead to excessive dilatation of the ventricles, one of the hallmarks of congestive heart failure. Therefore, it is important to better understand the wound-healing process in the heart and to develop new therapeutic agents that target the infarct area in order to maintain an adequate cardiac function. One of these potential novel therapeutic targets is Wnt signaling. Wnt signaling plays an important role in embryonic myocardial development but in the adult heart the pathway is thought to be silent. However, there is increasing evidence that components of the Wnt pathway are re-expressed during cardiac repair, implying a regulatory role. Recently, several studies have been published where the effect of interventions in Wnt signaling on infarct healing has been studied. In this review, we will summarize the results of these studies and discuss the effects of these interventions on the different cell types that are involved in the wound healing process.

Figure 1

Different statuses of the Wnt/Frizzled signaling cascade. (A) Wnt/Frizzled signaling is off when the Frizzled receptor is not engaged by a Wnt protein. Hence, the β-catenin degradation complex consisting of GSK-3β, Axin, APC and CK1 phosphorylates β-catenin at Ser/Thr residues, which ubiquitinates the latter and leads to degradation of it. As a result, β-catenin cannot enter the nucleus and activate transcription of target genes. (B) Upon binding of Wnt to the Frizzled receptor and co-localization of the LRP receptor, Dvl is activated, which disrupts the destruction complex. Now, β-catenin is accumulating in the cytoplasm and can enter the nucleus where it activates the TCF/LEF proteins and thereby activates the transcription of a broad range of genes. (C) Wnt proteins are prevented from binding to the Frizzled receptor by blockade of the cysteine-rich binding domains by UM206. In addition, the endogenous antagonist DKK prevents the LRP co-receptor from co-localization with the Frizzled receptor, thereby blocking the signaling transduction. sFRPs can scavenge Wnt proteins, which can reduce active Wnt signaling. Via all these mechanisms, β-catenin is prevented from entering the nucleus and transcription is not initiated.

Figure 2

Potential targets of modulations in Wnt signaling to improve cardiac repair. Interventions in Wnt/Frizzled signaling can modulate several processes such as neovascularization, myofibroblast differentiation and stem cell proliferation/differentiation, which can all contribute to improved healing of the scar, preservation of cardiac function and thereby prevent development of congestive heart failure (CHF).