WNT Signaling in Cardiac and Vascular Disease

Foulquier, Sébastien; Daskalopoulos, Evangelos P.; Lluri, Gentian; Hermans, Kevin C.M.; Deb, Arjun; Blankesteijn, W. Matthijs

doi:10.1124/pr.117.013896

Cited by 288 publications

(263 citation statements)

References 643 publications

(862 reference statements)

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“…Both canonical and noncanonical Wnt-signaling pathways are involved in the phenotypic transition of VSMCs, and they play important roles in the progression of VC and lead to cardiovascular disease [92,93]. The canonical Wnt signaling and its downstream target genes are required for the differentiation of osteoblasts.…”

Section: The Interplay Between Sirt1 and The Wnt/β-catenin Pathway Inmentioning

confidence: 99%

Sirtuin-1 and Its Relevance in Vascular Calcification

Liao

Hou

et al. 2020

IJMS

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Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.

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Section: The Interplay Between Sirt1 and The Wnt/β-catenin Pathway Inmentioning

confidence: 99%

Sirtuin-1 and Its Relevance in Vascular Calcification

Liao

Hou

et al. 2020

IJMS

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“…Dkk1 is well known as an inhibitor of canonical Wnt/β-catenin signaling cascade, and acts by inducing endocytosis of the ternary Dkk1-LRP5/6-Kremen1 complex or by competitively binding to the Wnt co-receptor (Foulquier et al, 2018). Dkk1 destabilizes atherosclerotic lesions and promotes plaque formation and vulnerability through inhibiting Wnt signaling during atherosclerosis (Di et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The abnormal regulation of Wnt/β-catenin pathway is associated with a variety of cardiovascular diseases. The canonical Wnt/β-catenin signaling pathway is indispensable for heart development (Andersen et al, 2018;Foulquier et al, 2018;Merks et al, 2018;Sadahiro et al, 2018). Deficiency of β-catenin leads to a failure in the differentiation of cardiac components and heart regeneration (Ozhan and Weidinger, 2015;Ruiz-Villalba et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

Liu

et al. 2019

Journal of Cell Science

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The cancer clinical therapy of doxorubicin (Dox) treatment is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding and best-studied member of the Dkk family, functions as an antagonist of canonical Wnt/β-catenin. Dkk1 is considered to play a broad role in a variety of biological processes, but its effects on Dox-induced cardiomyopathy are poorly understood. Here, we found that the level of Dkk1 was significantly increased in Dox-treated groups, and this increase exacerbated Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction. Overexpressing Dkk1 aggravated Dox-induced cardiotoxicity in H 9 C 2 cells. Similar results were detected when adding active Dkk1 protein extracellularly. Conversely, adding specific antibody blocking extracellular Dkk1 attenuated the cardiotoxic response to Dox. Adenovirus encoding Dkk1 was transduced through intramyocardial injection and exacerbated Dox-induced cardiomyocyte apoptosis, mitochondrial damage and heart injury in vivo. Furthermore, Wnt/βcatenin signaling was inhibited during Dox-induced cardiotoxicity, and the re-activation of β-catenin prevented the effect of overexpressed Dkk1 and Dox-induced cardiotoxicity. In conclusion, these results reveal the crucial role of the Dkk1-Wnt/β-catenin signaling axis in the process of Dox-induced cardiotoxicity and provide novel insights into the potential mechanism of cardiomyopathy caused by clinical application of Dox.

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“…Modulation at the Receptor Level. Activation of WNT signaling has been convincingly demonstrated during the wound-healing process following MI (Foulquier et al, 2018).…”

Section: Wnt Signalingmentioning

confidence: 95%

“…Many of the mechanisms involved in the wound-healing response (inflammation, angiogenesis, fibrosis, reinnervation, etc.) have been shown to respond to interventions in WNT signaling as well, as reviewed elsewhere (Dawson et al, 2013;Foulquier et al, 2018). It is quite conceivable that in the plethora of signaling taking place in the healing infarct, inhibition of WNT signaling may tip the balance toward conditions in which other pathways become active to stimulate CM proliferation.…”

Section: Wnt Signalingmentioning

confidence: 99%

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

Blankesteijn

2019

Mol Pharmacol

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Myocardial infarction is a frequent cardiovascular event and a major cause for cardiomyocyte loss. In adult mammals, cardiomyocytes are traditionally considered to be terminally differentiated cells, unable to proliferate. Therefore, the woundhealing response in the infarct area typically yields scar tissue rather than newly formed cardiomyocytes. In the last decade, several lines of evidence have challenged the lack of proliferative capacity of the differentiated cardiomyocyte: studies in zebrafish and neonatal mammals have convincingly demonstrated the regenerative capacity of cardiomyocytes. Moreover, multiple signaling pathways have been identified in these models that-when activated in adult mammalian cardiomyocytes-can reactivate the cell cycle in these cells. However, cardiomyocytes frequently exit the cell cycle before symmetric division into daughter cells, leading to polyploidy and multinucleation. Now that there is more insight into the reactivation of the cell cycle machinery, other prerequisites for successful symmetric division of cardiomyocytes, such as the control of sarcomere disassembly to allow cytokinesis, require more investigation. This review aims to discuss the signaling pathways involved in cardiomyocyte proliferation, with a specific focus on wingless/int-1 protein signaling. Comparing the conflicting results from in vitro and in vivo studies on this pathway illustrates that the interaction with other cells and structures around the infarct is likely to be essential to determine the outcome of these interventions. The extensive crosstalk with other pathways implicated in cardiomyocyte proliferation calls for the identification of nodal points in the cell signaling before cardiomyocyte proliferation can be moved forward toward clinical application as a cure of cardiac disease. SIGNIFICANCE STATEMENT Evidence is mounting that proliferation of pre-existing cardiomyocytes can be stimulated to repair injury of the heart. In this review article, an overview is provided of the different signaling pathways implicated in cardiomyocyte proliferation with emphasis on wingless/int-1 protein signaling, crosstalk between the pathways, and controversial results obtained in vitro and in vivo.

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WNT Signaling in Cardiac and Vascular Disease

Cited by 288 publications

References 643 publications

Sirtuin-1 and Its Relevance in Vascular Calcification

Sirtuin-1 and Its Relevance in Vascular Calcification

Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

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