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Wnt Signaling in Cardiac Disease

Kevin CM Hermans, W Matthijs Blankesteijn

10.1002/cphy.c140060

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



ABSTRACT

Wnt signaling encompasses multiple and complex signaling cascades and is involved in many developmental processes such as tissue patterning, cell fate specification, and control of cell division. Consequently, accurate regulation of signaling activities is essential for proper embryonic development. Wnt signaling is mostly silent in the healthy adult organs but a reactivation of Wnt signaling is generally observed under pathological conditions. This has generated increasing interest in this pathway from a therapeutic point of view. In this review article, the involvement of Wnt signaling in cardiovascular development will be outlined, followed by its implication in myocardial infarct healing, cardiac hypertrophy, heart failure, arrhythmias, and atherosclerosis. The initial experiments not always offer consensus on the effects of activation or inactivation of the pathway, which may be attributed to (i) the type of cardiac disease, (ii) timing of the intervention, and (iii) type of cells that are targeted. Therefore, more research is needed to determine the exact implication of Wnt signaling in the conditions mentioned above to exploit it as a powerful therapeutic target. © 2015 American Physiological Society. Compr Physiol 5:1183‐1209, 2015.

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Figure 1. Figure 1. Crystal structure of Xenopus Wnt8 in complex with the cysteine rich domain (CRD) of Frizzled8 (Fzd8). The structure of the Wnt protein mimics the palm of a hand with an index finger at the C‐terminal domain and a thumb and the N‐terminal domain. The index finger and the palmitic acid both make contact with the CRD leaving a gap in the middle that might be important for Wnt/Frizzled specificity.
Figure 2. Figure 2. Schematic overview of the noncanonical signaling pathways. (A) In the planar cell polarity pathway, Wnt binds to Frizzled and activates signaling independent from low‐density lipoprotein receptor‐related protein (LRP) 5/6. Dishevelled (Dvl) activates the small GTPases Rho and RAC that thereafter activate Rho kinase (ROCK) and c‐jun N‐terminal kinase (JNK) respectively. (B) The Wnt/Ca2+ signals through G‐proteins that activate phospholipase‐C (PLC). PLC causes a rise in intracellular Ca2+ that activates the Ca2+‐dependent enzymes calcineurin, calcium/calmodulin‐dependent kinase II (CaMKII), and protein kinase C (PKC). These enzymes can modulate the translocation of NFAT to the nucleus.
Figure 3. Figure 3. Schematic overview of the canonical/β‐catenin‐mediated signaling pathway. In the “off state” (left) the Frizzled receptor is not engaged by a Wnt protein. Wnts can also be scavenged by secreted frizzled‐related proteins (sFRP), thereby inhibiting signaling. In addition, canonical signaling is also prevented by inhibition of the low‐density lipoprotein receptor‐related protein (LRP) 5/6 coreceptors by Dickkopf (DKK). In the absence of signaling, the β‐catenin degradation complex consisting of glycogen synthase kinase 3β (GSK3β), Axin, adenomatous polyposis coli (APC), and casein kinase 1 (CK1) phosphorylates β‐catenin, which causes ubiquitination and degradation of the latter. In this way, cytoplasmic β‐catenin levels are kept low and prevent the protein from entering the nucleus to activate gene transcription. In the “on state” (right) Wnt binds to Frizzled and activates signaling together with the LRP coreceptors. Now Dvl is mobilized and inactivates the β‐catenin degradation complex. Hence, β‐catenin accumulates in the cytoplasm and is able to translocate to the nucleus where it interacts with the TCF/LEF transcription factors. These factors induce the transcription of Wnt‐responsive genes.
Figure 4. Figure 4. Effect of Wnt signaling on sprouting angiogenesis. In sprouting angiogenesis, tip cells guide the sprout into the required direction whereas the following sprout cells can proliferate and form the new vessel. Activation of Wnt signaling promotes the proliferation of stalk cells and their organization into tube‐like structures. There is no evidence for a direct effect of Wnt signaling on tip cells, but Wnt signaling can affect these cells indirectly by augmenting the expression of Delta‐like ligand 4 (Dll4) in the stalk cells, which can activate the Notch signaling in the tip cells in a paracrine way, thereby inducing a stalk‐like phenotype in these cells.
Figure 5. Figure 5. Expression patterns of Wnt signaling components ± 1 week after MI in experimental animal models. A green arrow indicates an upregulation, a red arrow downregulation and “=” indicates no difference in gene expression. Fzd; Frizzled, sFRP; secreted frizzled‐related protein.
Figure 6. Figure 6. Hypertrophic response of the heart to different types of stress. Physiological hypertrophy is induced by pregnancy or intensive exercise training. Cardiomyocytes increase in thickness and in length. This type of hypertrophy is reversible. Concentric hypertrophy is the result of disorders that cause pressure overload and goes along with thickening of the cardiomyocytes, reduced left ventricular volume, increased fibrosis, and stiffening of the heart muscle and is usually not reversible. Prolonged pressure overload can result in dilated cardiomyopathy in which the heart muscle is overstretched and loses contractile force. In addition, chronic volume overload can also result in dilated cardiomyopathy.
Figure 7. Figure 7. Signaling pathways leading to pathological and physiological hypertrophy. In pathological hypertrophy (A), neurohumoral regulators such as angiotensin II (AngII), endothelin‐1 (ET‐1), and catecholamines like phenylephrine (PE), activate Phospholipase‐C (PLC) through G‐protein‐coupled receptors. Activated PLC hydrolyzes PIP2 into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 causes a rise in intracellular Ca2+, which activates calcineurin that in turn dephosphorylates NFAT. DAG activates protein kinase C (PKC) that induces hypertrophic gene transcription together with NFAT. Physiological hypertrophy (B) is initiated by growth factors such as growth hormone (GH) and insulin‐like growth factor (IGF) that provoke phosphoinositide 3'kinase (PI3K) signaling. Activated PI3K phosphorylates PIP2 to PIP3 that subsequently activates Akt through phosphorylation. Activated Akt inactivates glycogen synthase kinase 3β (GSK3β) by phosphorylation. Now, GSK3β can no longer inactivate transcription factors such as NFAT and GATA4, which causes translocation to the nucleus and subsequent hypertrophic gene transcription.
Figure 8. Figure 8. A schematic representation of an intercalated disk between adjacent cardiomyocytes. Mechanical coupling of the cardiomyocytes is coordinated by adherens junctions and desmosomes. Gap junctions are necessary for rapid current propagation through the myocardium to induce cardiac contraction.


Figure 1. Crystal structure of Xenopus Wnt8 in complex with the cysteine rich domain (CRD) of Frizzled8 (Fzd8). The structure of the Wnt protein mimics the palm of a hand with an index finger at the C‐terminal domain and a thumb and the N‐terminal domain. The index finger and the palmitic acid both make contact with the CRD leaving a gap in the middle that might be important for Wnt/Frizzled specificity.


Figure 2. Schematic overview of the noncanonical signaling pathways. (A) In the planar cell polarity pathway, Wnt binds to Frizzled and activates signaling independent from low‐density lipoprotein receptor‐related protein (LRP) 5/6. Dishevelled (Dvl) activates the small GTPases Rho and RAC that thereafter activate Rho kinase (ROCK) and c‐jun N‐terminal kinase (JNK) respectively. (B) The Wnt/Ca2+ signals through G‐proteins that activate phospholipase‐C (PLC). PLC causes a rise in intracellular Ca2+ that activates the Ca2+‐dependent enzymes calcineurin, calcium/calmodulin‐dependent kinase II (CaMKII), and protein kinase C (PKC). These enzymes can modulate the translocation of NFAT to the nucleus.


Figure 3. Schematic overview of the canonical/β‐catenin‐mediated signaling pathway. In the “off state” (left) the Frizzled receptor is not engaged by a Wnt protein. Wnts can also be scavenged by secreted frizzled‐related proteins (sFRP), thereby inhibiting signaling. In addition, canonical signaling is also prevented by inhibition of the low‐density lipoprotein receptor‐related protein (LRP) 5/6 coreceptors by Dickkopf (DKK). In the absence of signaling, the β‐catenin degradation complex consisting of glycogen synthase kinase 3β (GSK3β), Axin, adenomatous polyposis coli (APC), and casein kinase 1 (CK1) phosphorylates β‐catenin, which causes ubiquitination and degradation of the latter. In this way, cytoplasmic β‐catenin levels are kept low and prevent the protein from entering the nucleus to activate gene transcription. In the “on state” (right) Wnt binds to Frizzled and activates signaling together with the LRP coreceptors. Now Dvl is mobilized and inactivates the β‐catenin degradation complex. Hence, β‐catenin accumulates in the cytoplasm and is able to translocate to the nucleus where it interacts with the TCF/LEF transcription factors. These factors induce the transcription of Wnt‐responsive genes.


Figure 4. Effect of Wnt signaling on sprouting angiogenesis. In sprouting angiogenesis, tip cells guide the sprout into the required direction whereas the following sprout cells can proliferate and form the new vessel. Activation of Wnt signaling promotes the proliferation of stalk cells and their organization into tube‐like structures. There is no evidence for a direct effect of Wnt signaling on tip cells, but Wnt signaling can affect these cells indirectly by augmenting the expression of Delta‐like ligand 4 (Dll4) in the stalk cells, which can activate the Notch signaling in the tip cells in a paracrine way, thereby inducing a stalk‐like phenotype in these cells.


Figure 5. Expression patterns of Wnt signaling components ± 1 week after MI in experimental animal models. A green arrow indicates an upregulation, a red arrow downregulation and “=” indicates no difference in gene expression. Fzd; Frizzled, sFRP; secreted frizzled‐related protein.


Figure 6. Hypertrophic response of the heart to different types of stress. Physiological hypertrophy is induced by pregnancy or intensive exercise training. Cardiomyocytes increase in thickness and in length. This type of hypertrophy is reversible. Concentric hypertrophy is the result of disorders that cause pressure overload and goes along with thickening of the cardiomyocytes, reduced left ventricular volume, increased fibrosis, and stiffening of the heart muscle and is usually not reversible. Prolonged pressure overload can result in dilated cardiomyopathy in which the heart muscle is overstretched and loses contractile force. In addition, chronic volume overload can also result in dilated cardiomyopathy.


Figure 7. Signaling pathways leading to pathological and physiological hypertrophy. In pathological hypertrophy (A), neurohumoral regulators such as angiotensin II (AngII), endothelin‐1 (ET‐1), and catecholamines like phenylephrine (PE), activate Phospholipase‐C (PLC) through G‐protein‐coupled receptors. Activated PLC hydrolyzes PIP2 into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 causes a rise in intracellular Ca2+, which activates calcineurin that in turn dephosphorylates NFAT. DAG activates protein kinase C (PKC) that induces hypertrophic gene transcription together with NFAT. Physiological hypertrophy (B) is initiated by growth factors such as growth hormone (GH) and insulin‐like growth factor (IGF) that provoke phosphoinositide 3'kinase (PI3K) signaling. Activated PI3K phosphorylates PIP2 to PIP3 that subsequently activates Akt through phosphorylation. Activated Akt inactivates glycogen synthase kinase 3β (GSK3β) by phosphorylation. Now, GSK3β can no longer inactivate transcription factors such as NFAT and GATA4, which causes translocation to the nucleus and subsequent hypertrophic gene transcription.


Figure 8. A schematic representation of an intercalated disk between adjacent cardiomyocytes. Mechanical coupling of the cardiomyocytes is coordinated by adherens junctions and desmosomes. Gap junctions are necessary for rapid current propagation through the myocardium to induce cardiac contraction.
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Article Title: Wnt Signaling in Cardiac Disease
 

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Kevin CM Hermans, W Matthijs Blankesteijn. Wnt Signaling in Cardiac Disease. Compr Physiol 2015, 5: 1183-1209. doi: 10.1002/cphy.c140060