Research Article: Wnt signaling pathways in myocardial infarction and the therapeutic effects of Wnt pathway inhibitors

Date Published: July 12, 2018

Publisher: Nature Publishing Group UK

Author(s): Wen-bin Fu, Wei Eric Wang, Chun-yu Zeng.

http://doi.org/10.1038/s41401-018-0060-4

Abstract

Myocardial infarction (MI) is one of the most serious health threats, resulting in huge physical and economic burdens worldwide. Wnt signaling pathways play an important role in developmental processes such as tissue patterning, cell differentiation and cell division. Appropriate regulation of the activities of Wnt signaling pathways is also important for heart development and healing in post-MI heart. Moreover, Wnt pathway inhibitors have been identified as novel antitumor drugs and applied in ongoing clinical trials. This research progress has generated increasing interests for investigating the effects of Wnt pathway inhibitors on MI healing. In this short review, we summarize the roles of Wnt signaling pathways in post-MI heart and the therapeutic effects of Wnt pathway inhibitors on MI, and discuss the underlying mechanisms of Wnt pathway inhibitors in cardiac repairing.

Partial Text

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality and threatens human health worldwide [1]. In spite of the therapeutic function of drugs such as adrenoceptor blockers, calcium antagonists and renin-angiotensin system inhibitors [2], the progression of MI and pathological remodeling are still irreversible. Recent studies agree on the fact that adult mammalian cardiomyocytes are able to regenerate but with a very limited efficacy [3]. This fact evokes further studies to discover novel drug candidates that aim to reduce pathological remodeling and stimulate cardiac regeneration.

Wnt was first discovered as Int-1, and then it was found to be a homologous gene of the wingless gene in Drosophila [11]. Wnt signaling pathways include the canonical Wnt/β-catenin pathway, non-canonical Wnt/planar cell polarity (PCP) pathway and Wnt/Ca2+ dependent pathway (Fig. 1) [6]. All three pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which conducts signal to the Dishevelled (Dvl) protein inside the cell [12]. The secretion of Wnt proteins is dependent on palmitoylation by Porcupine [13]. Another docking protein family named low-density lipoprotein receptor (LRP) is also found in the Wnt/Frizzled complex [14]. In the canonical Wnt pathway, β-catenin is phosphorylated and degraded by a destruction complex, including Axin, glycogen synthase kinase 3β (GSK3β), adenomatous polyposis coli (APC), and casein kinase 1α (CK1α). Wnt stimulation phosphorylates Dvl protein, dissociates β-catenin and induces the nuclear translocation of β-catenin, leading to its interaction with TCF/LEF transcription factors and gene transcription [15]. In the Wnt/PCP pathway, Dvl phosphorylation results in RhoA/ROCK and Rac/Jnk/NFAT pathway activation [16]. In the Wnt/Ca2+ pathway, phospholipase C (PLC) is activated and induces the accumulation of intracellular Ca2+, leading to the activation of calmodulin-dependent kinase II (CamKII), calcineurin and protein kinase C (PKC) [17].Fig. 1Wnt signaling pathways and the intervention targets of Wnt pathway inhibitors. The secretion of Wnt proteins is dependent on palmitoylation by Porcupine. Frizzled and low-density lipoprotein receptor (LRP) proteins are membrane receptors for binding Wnt proteins. In the canonical Wnt pathway, Wnt binding leads to β-catenin nuclear translocation (after dissociation from a complex with Axin, glycogen synthase kinase 3β (GSK3β), adenomatous polyposis coli (APC) and casein kinase 1α (CK1α)), causing its interaction with TCF/LEF transcription factors and gene transcription. In the Wnt/PCP pathway, Wnt binding results in RhoA/ROCK and Rac/Jnk/NFAT pathway transduction. In the Wnt/Ca2+ pathway, Wnt binding leads to phospholipase C (PLC) activation and the accumulation of intracellular Ca2+, which then leads to the activation of calmodulin-dependent kinase II (CamKII), calcineurin and protein kinase C (PKC). UM206 targets the Frizzled receptor family; pyrvinium inhibits Axin degradation; ICG-001 inhibits the interaction between β-catenin and CBP; and WNT-974, CGX-1321 and GNF-6231 are porcupine inhibitors

Pyrvinium is a drug approved by the FDA and identified as a Wnt inhibitor by inhibiting Axin degradation and stabilizing β-catenin, which can increase Ki67+ cardiomyocytes in the peri-infarct area and alleviate cardiac remodeling in a mouse model of MI [52]. UM206 is a peptide with a high homology to Wnt-3a/5a, and acts as an antagonist for Frizzled proteins to inhibit Wnt signaling pathway transduction. UM206 could reduce infarct size, increase the numbers of capillaries, decrease myofibroblasts in infarct area of post-MI heart, and ultimately suppress the development of heart failure [53]. ICG-001, which specifically inhibits the interaction between β-catenin and CBP in the Wnt canonical signaling pathway, can promote the differentiation of epicardial progenitors, thereby contributing to myocardial regeneration and improving cardiac function in a rat model of MI [54]. Small molecules invaliding Porcupine have been further studied, such as WNT-974, GNF-6231 and CGX-1321. WNT-974 decreases fibrosis in post-MI heart, with a mechanism of preventing collagen production in cardiomyocytes by blocking secretion of Wnt-3, a pro-fibrotic agonist, from cardiac fibroblasts and its signaling to cardiomyocytes [8]. The phosphorylation of DVL protein is decreased in both the canonical and non-canonical Wnt signaling pathways by WNT-974 administration [8]. GNF-6231 prevents adverse cardiac remodeling in a mouse model of MI by inhibiting the proliferation of interstitial cells, increasing the proliferation of Sca1+ cardiac progenitors and reducing the apoptosis of cardiomyocytes [9]. Similarly, we demonstrate that CGX-1321, which has also been applied in a phase I clinical trial to treat solid tumors (NCT02675946), inhibits both canonical and non-canonical Wnt signaling pathways in post-MI heart. CGX-1321 promotes cardiac function by reducing fibrosis and stimulating cardiomyocyte proliferation-mediated cardiac regeneration in a Hippo/YAP-independent manner [10]. These reports implicate that Wnt pathway inhibitors are a class of potential drugs for treating MI through complex mechanisms, including reducing cardiomyocyte death, increasing angiogenesis, suppressing fibrosis and stimulating cardiac regeneration.

Both the canonical and non-canonical Wnt signaling pathways are essential for heart development and play an important role in adult heart with MI injury. The inhibition of Wnt signaling pathways has been demonstrated to be beneficial in MI via improving cardiac remodeling. These Wnt inhibitory compounds have been proven to be safe in clinical trials and can be potential drugs for treating MI. However, novel Wnt pathway inhibitors with minimized toxicity and a more exclusive effect on the heart are still needed.

 

Source:

http://doi.org/10.1038/s41401-018-0060-4