Molecular strategies for modulating Wnt signaling

Gustafson, Carl T.; Mamo, Tewodros; Maran, Avudaiappan; Yaszemski, Michael J.

doi:10.2741/4477

Cited by 8 publications

(8 citation statements)

References 143 publications

(163 reference statements)

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“…We recently demonstrated increased systemic and myocardial Wnt5a in relation to PH and right ventricular failure in patients with left ventricular heart failure 15,16 . Modulation of Wnt signalling could therefore potentially represent a novel therapeutic option in PH, and several approaches targeting these pathways are under investigation 17,18 . However, data on the regulation of Wnt pathways in clinical precapillary PH are scarce.…”

Section: Introductionmentioning

confidence: 99%

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Circulating regulators of the wingless pathway in precapillary pulmonary hypertension

et al. 2021

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Background and objective Dysregulated Wnt signalling has been implicated in pulmonary hypertension (PH). We hypothesized that plasma levels of secreted Wnt proteins would be increased in patients with precapillary PH, correlate with indices of vascular resistance and cardiac function and give information on long‐term prognosis. Methods We measured the Wnt ligand Wnt5a and secreted Wnt antagonists Dickkopf (DKK) DKK1, DKK3, secreted frizzled‐related protein 3 (sFRP3), Wnt inhibitory factor‐1 (WIF1) and sclerostin (SOST) in 106 patients with precapillary PH and 40 healthy controls. A second sample was obtained after a median of 4 months (n = 52). During a median of 90 months follow‐up, 67 patients died. Results Our main findings were (i) Precapillary PH is characterized by enhanced systemic Wnt activity as reflected by elevated plasma levels of Wnt5a and secreted antagonists irrespective of diagnostic subgroups. (ii) WIF1 and in particular Wnt5a correlated with pulmonary vascular resistance and cardiac dysfunction. (iii) High levels of Wnt5a, sFRP3, DKK3 and WIF1 were associated with poor prognosis in age‐ and sex‐adjusted analysis (hazard ratios per log/SD change ~1.4) and for DKK3 after further adjustment with right arterial pressure, pulmonary oxygen saturation, cardiac index, N‐terminal pro B‐type natriuretic peptide and peak oxygen uptake (VO2). Finally, an elevation of Wnt5a and DKK3 during follow‐up was independently associated with poor prognosis. Conclusion Our data indicate that Wnt signalling pathways could be implicated in the pathogenesis of precapillary PH, and that some of the Wnt‐related molecules (i.e., Wnt5a and DKK3) should be further investigated in these patients.

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Section: Introductionmentioning

confidence: 99%

“…15,16 Modulation of Wnt signalling could therefore potentially represent a novel therapeutic option in PH, and several approaches targeting these pathways are under investigation. 17,18 However, data on the regulation of Wnt pathways in clinical precapillary PH are scarce.…”

Section: Introductionmentioning

confidence: 99%

Circulating regulators of the wingless pathway in precapillary pulmonary hypertension

et al. 2021

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“…The majority of Wnt ligands and Frizzled receptor have been detected in first trimester placental tissue (9). The Wnt pathways also consists of a number of endogenous secreted pathway modulators including agonists such as Rspondins (RSPOs) which act synergistically with Wnt ligands to enhance signaling (10) and antagonists such as dickkopf (DKKs) and the secreted frizzled related proteins (sFRPs), that regulate both canonical and non-canonical Wnt signaling by binding various ligands and receptors (11,12). In the context of PE, increased expression of DKK1 and sFRP4 has been detected in placental tissue (13,14) leading to decreased βcatenin, emphasizing a role for these secreted Wnt antagonists in dysregulated canonical Wnt signaling in PE (8).…”

Section: Text Introductionmentioning

confidence: 99%

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies

Ueland

Estensen

Grindheim³

et al. 2020

Journal of Hypertension

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Objective: Preeclampsia is a syndrome characterized by hypertension and poor placental development. The developmental Wnt pathway plays an important role in placental development and we hypothesized that Wnt signaling would be dysregulated in preeclampsia.Methods: To elucidate aberrations in the Wnt signaling pathway we conducted a pathway analysis on placental mRNA in late-onset preeclampsia and normal pregnancy from the STORK study (n=10 in each group, RNAseq) to identify differentially expressed genes. In addition, we compared circulating levels of secreted Wnt agonists and antagonists at term pregnancy and 6 months post-partum from an acute preeclampsia study (preeclampsia n=34, normal pregnancy n=61).Results: We found circulating and placental mRNA levels of the secreted Wnt agonist RSPO3 at term elevated in preeclampsia. Increased plasma RSPO3 was associated with high mean arterial pressure. Further, pathway analysis of placental tissue revealed elevated mRNA levels of upstream ligands WNT6 and WNT10A and frizzled receptors 2 and 4 in preeclampsia and downstream activation of the non-canonical Ca 2+ /NFAT pathway. Finally, plasma DKK3 was decreased in preeclampsia 6 months post-partum. Conclusion:We identify a potential role for RSPO3 and activation of non-canonical Wnt signaling in preeclampsia.

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“…Myofibroblasts can express Wnt2b, Wnt4, and Wnt5, which lead to the activation of the noncanonical pathway, driving cellular polarity and motility and therefore supporting the differentiation of IECs 17 . Although Wnt ligands and Fz receptors activate Wnt signaling, the pathway can be negatively regulated by antagonistic mechanisms, such as the secreted Fz-related proteins 18, 19. Secreted Fz-related proteins are secreted predominantly by mesenchymal cells in close proximity to Wnt-producing intestinal stem cells to regulate Wnt signalling 15 …”

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confidence: 99%

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Martini

Krug

Siegmund

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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200

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The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel disease (IBD), such as ulcerative colitis or Crohn’s disease. For a long time, research into the pathophysiology of IBD has been focused on immune cell–mediated mechanisms. Recent evidence, however, suggests that the intestinal epithelium might play a major role in the development and perpetuation of IBD. It is now clear that IBD can be triggered by disturbances in epithelial barrier integrity via dysfunctions in intestinal epithelial cell–intrinsic molecular circuits that control the homeostasis, renewal, and repair of intestinal epithelial cells. The intestinal epithelium in the healthy individual represents a semi-permeable physical barrier shielding the interior of the body from invasions of pathogens on the one hand and allowing selective passage of nutrients on the other hand. However, the intestinal epithelium must be considered much more than a simple physical barrier. Instead, the epithelium is a highly dynamic tissue that responds to a plenitude of signals including the intestinal microbiota and signals from the immune system. This epithelial response to these signals regulates barrier function, the composition of the microbiota, and mucosal immune homeostasis within the lamina propria. The epithelium can thus be regarded as a translator between the microbiota and the immune system and aberrant signal transduction between the epithelium and adjacent immune cells might promote immune dysregulation in IBD. This review summarizes the important cellular and molecular barrier components of the intestinal epithelium and emphasizes the mechanisms leading to barrier dysfunction during intestinal inflammation.

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Molecular strategies for modulating Wnt signaling

Cited by 8 publications

References 143 publications

Circulating regulators of the wingless pathway in precapillary pulmonary hypertension

Circulating regulators of the wingless pathway in precapillary pulmonary hypertension

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies

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