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

Hermans KC, Daskalopoulos EP, Blankesteijn WM - Fibrogenesis Tissue Repair (2012)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, 50 Universiteitssingel, 6229ER Maastricht, PO Box 616 6200MD, Maastricht, The Netherlands. wm.blankesteijn@maastrichtuniversity.nl.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3472244&req=5

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.

Mentions: β-Catenin is the second messenger of the canonical Wnt signaling pathway and it is the most studied of all. In the absence of the ligand (Wnt), several factors including the adenomatous polyposis coli (APC), casein kinase 1 (CK1) and Axin activate glycogen synthase kinase (GSK) 3β. This in turn phosphorylates several Ser/Thr residues of β-catenin, which leads to the ubiquitination of the latter. Hence, β-catenin is degraded and cannot enter the nucleus in order to modulate gene transcription (Figure1A). On the other hand, upon activation of the Frizzled receptor and the LRP co-receptor by Wnt, the complex (Wnt-Frizzled-LRP) directly activates the first downstream protein, Dishevelled (Dvl). Dvl directly interacts with Axin and breaks down the ‘destruction complex’ comprising of APC, Axin, CK1 and GSK-3β. In this case, β-catenin is no longer degraded but it accumulates in the cytoplasm and enters the nucleus where it binds and activates the T-cell factor/lymphoid enhancer factor (TCF/LEF) proteins. These proteins can bind to DNA and activate the transcription of a wide range of genes, including c-myc, cyclin D1, c-jun, fra-1 [30] and many others (Figure1B). The activation (or not) of these target genes is of paramount importance, since they regulate: cell growth and apoptosis (c-myc) [31], cell proliferation, differentiation and response to various stimuli (c-jun) [32], cell motility and invasion (fra-1) [33] and cell cycle (cyclin D1) [34].


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

Hermans KC, Daskalopoulos EP, Blankesteijn WM - Fibrogenesis Tissue Repair (2012)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472244&req=5

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.
Mentions: β-Catenin is the second messenger of the canonical Wnt signaling pathway and it is the most studied of all. In the absence of the ligand (Wnt), several factors including the adenomatous polyposis coli (APC), casein kinase 1 (CK1) and Axin activate glycogen synthase kinase (GSK) 3β. This in turn phosphorylates several Ser/Thr residues of β-catenin, which leads to the ubiquitination of the latter. Hence, β-catenin is degraded and cannot enter the nucleus in order to modulate gene transcription (Figure1A). On the other hand, upon activation of the Frizzled receptor and the LRP co-receptor by Wnt, the complex (Wnt-Frizzled-LRP) directly activates the first downstream protein, Dishevelled (Dvl). Dvl directly interacts with Axin and breaks down the ‘destruction complex’ comprising of APC, Axin, CK1 and GSK-3β. In this case, β-catenin is no longer degraded but it accumulates in the cytoplasm and enters the nucleus where it binds and activates the T-cell factor/lymphoid enhancer factor (TCF/LEF) proteins. These proteins can bind to DNA and activate the transcription of a wide range of genes, including c-myc, cyclin D1, c-jun, fra-1 [30] and many others (Figure1B). The activation (or not) of these target genes is of paramount importance, since they regulate: cell growth and apoptosis (c-myc) [31], cell proliferation, differentiation and response to various stimuli (c-jun) [32], cell motility and invasion (fra-1) [33] and cell cycle (cyclin D1) [34].

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, 50 Universiteitssingel, 6229ER Maastricht, PO Box 616 6200MD, Maastricht, The Netherlands. wm.blankesteijn@maastrichtuniversity.nl.

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.

No MeSH data available.


Related in: MedlinePlus