Nuclear Level Effects on inflammation were not reported in any of the studies in which interventions at the nuclear level of WNT/-catenin signaling were investigated. 8. glycogen synthase kinase-3 (GSK3) and by intervening in the -catenin-mediated gene transcription. Interestingly, in several Velneperit 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. strong class=”kwd-title” Keywords: WNT signaling, myocardial infarction, infarct healing, in vivo, systematic review 1. Introduction Myocardial infarction (MI) is one of the most frequent cardiovascular events and a major cause of heart Velneperit failure (HF) development. Obstruction of the blood flow in coronary arteries results in a lack of oxygen and nutrients in the affected regions of the heart, causing the loss of cardiomyocytes (CMs) . Despite major progress in the treatment of acute MI, achieved by developing technology to re-establish the flow through the affected coronary arteries, there is still damage inflicted to the heart in a significant fraction of the patients. This is due to reperfusion injury, insufficient success of the procedure (the no-reflow phenomenon)  and late diagnosis of damage caused by plaque erosion, rather than plaque rupture . In the infarcted heart, a wound healing response is initiated, resulting in the replacement of the injured CMs by scar tissue. Over the last decades, this wound healing response has been studied extensively. 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). This granulation tissue eventually matures into scar tissue, which is characterized by large amounts of matrix with limited numbers of blood vessels and some myofibroblasts (MFs) . Numerous studies have been published in which signaling pathways that can modulate the different processes involved in infarct healing, are described . Moreover, there is increasing evidence that the damage can be repaired, at least in part, by inducing regeneration of CMs . These studies can form the basis for the development of novel therapies that improve the infarct healing and diminish the development of HF. One of the signaling pathways that has been extensively studied in the context of infarct healing is the WNT signaling pathway. After its initial discovery as a pathway involved in development and cancer, many other diseases and disease processes are now known to be regulated by WNT signaling . Our group was the first to describe the upregulation of the expression of the seven transmembrane (7TM) receptor Frizzled-2 (FZD2) in cardiac hypertrophy  and MI . In the meantime, a rapidly growing number of studies has been published in which WNT signaling was associated with many relevant processes in infarct healing, including CM apoptosis and regeneration, inflammation, angiogenesis and fibrosis . The activation of WNT signaling during cardiac remodeling has been confirmed in many studies. An elegant tool to investigate this is the use of WNT signaling reporter mice. Using an axin-2 promoter-driven LacZ expression model, Oerlemans et al.  were the first to show activation of WNT signaling in endothelial cells (ECs), fibroblasts, leukocytes and Sca+ progenitor cells in the border zone of the infarct from 7 days post-MI onwards. Similar results Velneperit were reported in other studies using axin-2 reporter mice [11,12], TOPGAL Velneperit reporter mice [13,14] and a -catenin-responsive construct of ferritin heavy chain and green fluorescent protein, carried by an adeno-associated virus serotype 9 (AAV9) . 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]. It has to be noted, however, that all of these reporter models only show the activation of WNT–catenin signaling, leaving the potential role of non–catenin mediated (non-canonical) WNT signaling in the regulation of infarct healing underexposed (the reader can refer to Section 2 for Rabbit polyclonal to PAX2 an explanation of the different WNT signaling pathways). The purpose of this systematic review is to provide a comprehensive overview of the studies on interventions in the WNT signaling in infarct healing. Because of the fact that the interplay between the various cell types involved in infarct healing is highly complex, we have decided to focus only on studies in which a direct intervention in WNT signaling was investigated in an in vivo model of MI (permanent coronary artery.