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.
Highlights
Myocardial infarction (MI) is one of the most frequent cardiovascular events and a major cause of heart failure (HF) development
The magnitude of the infarct was substantially increased in the DKK3 KO mice compared to their WT counterparts (WT: 37% vs. DKK3 KO: 48%) but an opposite effect was observed in the DKK3 Tg mice compared to their non-transgenic (NTG) littermates (NTG: 35% vs. DKK3 Tg: 23%)
Similar cardioprotective effects were demonstrated by a CM-specific genetic study, where overexpression of DKK3 in mice contributed to a substantial improvement in cardiac function (EF, fractional shortening (FS), dP/dt max and dP/dt min, end-systolic and -diastolic pressures) and attenuation of dilatation
Summary
Myocardial infarction (MI) is one of the most frequent cardiovascular events and a major cause of heart failure (HF) development. Following the death of CMs, an inflammatory response takes place first This is followed by the formation of granulation tissue, rich in newly-formed blood vessels and extracellular matrix-producing cardiac fibroblasts (CFs). Similar results were reported in other studies using axin-2 reporter mice [11,12], TOPGAL reporter mice [13,14] and a β-catenin-responsive construct of ferritin heavy chain and green fluorescent protein, carried by an adeno-associated virus serotype 9 (AAV9) [15] In many of these studies, the activation of WNT signaling in the epicardium was reported during the initial phases of infarct healing, underscoring the relevance of this tissue in the orchestration of infarct healing [16,17]. We have analyzed the effects of the interventions on critical parameters of infarct healing, including infarct size, cardiac function, inflammation, angiogenesis, fibrosis, and regeneration, in order to identify targets in the WNT signaling pathway with the most consistent beneficial effects
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