Effect of Interventions in WNT Signaling on Healing of Cardiac Injury: A Systematic Review

Abstract

The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words “WNT and myocardial and infarction”. We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3β (GSK3β) and by intervening in the β-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure.

Pharmacological suppression of the WNT signaling pathway attenuates age-dependent expression of the phenotype in a mouse model of arrhythmogenic cardiomyopathy

“…Activation of the WNT is known to prevent adipogenesis and enhance fibrosis, conversely, its suppression is known to provoke adipogenesis and attenuate fibrosis [ 26 , 39 , 40 ] . Likewise, data in the present study showing improvement in cardiac function and reduced apoptosis in the Myh6-Cre:Dsp W/F mice upon treatment with WNT974 are in accord with the role of the WNT in regulating apoptosis, cardiac remodeling, and cardiac function post-ischemic injury (reviewed in [ 41 ] ). Overall, the findings of the present study, validated by complementary methods, are in accord with the biological functions of the cWNT pathway and its role as a major transcriptional switch between adipogenesis and fibrogenesis as well as a regulator of cell death and cardiac function (reviewed in [ 41 ] ).…”

“…findings of the study on reduced myocardial fibrosis and apoptosis and increased myocardial adipocytes in an ACM model are in accord with the known biological effects of the WNT signaling pathway [26,39,40] . Activation of the WNT is known to prevent adipogenesis and enhance fibrosis, conversely, its suppression is known to provoke adipogenesis and attenuate fibrosis [26,39,40] .…”

“…findings of the study on reduced myocardial fibrosis and apoptosis and increased myocardial adipocytes in an ACM model are in accord with the known biological effects of the WNT signaling pathway [26,39,40] . Activation of the WNT is known to prevent adipogenesis and enhance fibrosis, conversely, its suppression is known to provoke adipogenesis and attenuate fibrosis [26,39,40] . Likewise, data in the present study showing improvement in cardiac function and reduced apoptosis in the Myh6-Cre:Dsp W/F mice upon treatment with WNT974 are in accord with the role of the WNT in regulating apoptosis, cardiac remodeling, and cardiac function post-ischemic injury (reviewed in [41] ).…”

Cardiac Fibrosis and Fibroblasts

“…Wnt signaling is reported to be one of the triggers of cardiac fibrosis. Although Wnt signaling is known to be activated in human cardiovascular disease [ 76 ], and the modulation of Wnt signaling has produced promising results in animal models of cardiac disease, the clinical application of Wnt signaling modulators has not yet been evaluated [ 77 ].…”

Porcupine inhibition: a novel disease-modifier target in arrhythmogenic cardiomyopathy

“…It has been described that other pathways are also affected as a consequence of the disruption of the intercellular junctions. The suppression of Hippo, a pathway closely interconnected with the canonical Wnt/β-catenin pathway, activates the expression of adipogenic genes [6] . In view of the complex interconnections between pathways, the simultaneous blockade of the canonical Wnt/β-catenin and Hippo pathways arises as an attractive strategy.…”