Genes & Diseases

A recent study delves deeper into understanding the mechanisms of AAA development and potential therapeutic strategies, focusing on the role of Wnt signaling. Researchers have observed that Wnt signaling, a pathway commonly reactivated in adults in various pathological conditions, including cardiovascular diseases, may be implicated in AAA development.

Abdominal aortic aneurysm (AAA), a common degenerative vascular disease, particularly afflicts men over the age of 60, with up to 8% affected. Characterized by the abnormal dilation of the abdominal aorta, AAA risks a potentially fatal rupture. Despite increasing research efforts, effective pharmaceutical strategies to curb aneurysm growth remain elusive.

In a study published in the journal of Genes & Diseases, researchers from Sant Pau Hospital Research Institute and Biomedical Research Institute Sant Pau scrutinized the Wnt signaling pathway's deregulation in human abdominal aortic aneurysm (AAA). This investigation revealed marked increases in WNT2 mRNA levels and moderate increments in WNT5A and WNT5B levels in aneurysmal samples as compared to healthy aortas. Further, a considerably higher presence of active β-catenin, the transcriptionally active form, was detected primarily in the inflammatory infiltrate of aneurysmal lesions, suggesting Wnt/β-catenin pathway activation in human AAA. Interestingly, the identified deregulation in Wnt signaling strikingly mirrored the scenario observed in aneurysmal aortas from AngII-infused ApoE−/− mice, a well-established AAA model. Based on these insights, the team hypothesized that the Wnt pathway might be a promising therapeutic target for AAA. Trials were carried out employing LGK974, a potent and specific porcupine inhibitor, and PRI-724, a selective inhibitor of β-catenin/CBP interaction, in AngII-infused ApoE−/− mice. While LGK974 was effective in reducing the vascular expression of the Wnt/β-catenin/TCF signaling target gene Axin2, it did not significantly curtail the progressive enlargement of the aortic diameter induced by AngII. Similarly, although PRI-724 modestly delayed the AngII-induced aortic diameter enlargement, the effect lacked statistical significance. In conclusion, the study underscores the significant role of the Wnt/β-catenin pathway in human and experimental AAA, but the therapeutic interventions tested, LGK974 and PRI-724, showed limited efficacy, with the exception of a minor reduction in aneurysm severity attributed to PRI-724.

The study underlines the multifaceted nature of AAA and the pressing need for efficacious treatments, signaling the potential for innovative avenues of intervention. This could potentially pave the way for groundbreaking therapeutic strategies to manage AAA. The researchers maintain that while the specific Wnt inhibitors tested may not have yielded significant benefits, the quest for alternative targets within this pathway could bear promising results for the future treatment of AAA.

Reference

Images

Image title: Activation of Wnt signaling in AAA and effect of LGK974 and PRI-724 on the formation of Ang II-induced AAA.

Image caption: Activation of Wnt signaling in AAA and effect of LGK974 and PRI-724 on the formation of Ang II-induced AAA. (A-B, left panels), Boxplots showing mRNA levels of WNT2, WNT5A and WNT5B (A), and their homologues in mice (B) analyzed by real-time PCR in abdominal aorta from healthy donors and patients with AAA [Donors (n = 9), AAA (n = 48); ∗P < 0.02 vs. Donors. Mann–Whitney test] or abdominal aorta from ApoE−/− mice infused with saline solution or AngII (1000 ng/kg/min for 28 days) (at least n = 9; ∗P < 0.01 vs. Saline. t-test). The box extends from the 25th to the 75th percentile, the median is indicated in horizontal line, and the whiskers represent the maximum and minimum values. (A-B, right panels), in A representative immunohistochemical analysis for active β-catenin (ABC) in abdominal aortas from AAA patients and healthy donors (black and red arrow heads indicate positive inflammatory cells and VSMC, respectively); in B representative immunoblot images showing ABC levels in abdominal aortas from animals as indicated above (levels of β-actin are shown as a loading control), and histogram showing the results (mean ± SEM) of the densitometric analysis [Saline (n = 4), AngII (n = 6); ∗P < 0.01 vs. Saline. Mann–Whitney test]. (C–F) ApoE−/− mice were infused with saline solution or AngII (1000 ng/kg/min for 28 days) and were treated or not with LGK974 (5 mg/kg/day). (C, left panel) representative images of aortas from each experimental group; (C, middle panel) data (mean ± SEM) from echocardiography analysis of the abdominal aortic diameter [Saline (n = 5), AngII (n = 14) and AngII/LGK974 (n = 8); ∗P < 0.05 vs. Saline. Two-way ANOVA]; (C, right panels) representative ultrasonographic frames after 28 days of AngII infusion. Transverse and longitudinal images taken at the level of the suprarenal aorta are shown. The aortic perimeter is indicated with a yellow line. (D) severity of AAA by experimental group (n as indicated in C middle panel). (E) Graph showing the survival rate of the experimental groups (Chi-square test). (F) Representative hematoxylin-eosin staining of abdominal aortic sections for each experimental group (bars: 200 μm). (G–J) ApoE−/− mice were infused with saline solution or AngII (1000 ng/kg/min for 28 days) and were treated or not with PRI-724 (15 mg/kg/day). (G, left panel) representative images of aortas from each experimental group; (G, middle panel) data (mean ± SEM) from echocardiography analysis of the abdominal aortic diameter [Saline (n = 5), AngII (n = 9) and AngII/PRI-724 (n = 9); ∗P < 0.05 vs. Saline. Two-way ANOVA]; (G, right panels) representative ultrasonographic frames after 28 days of AngII infusion as indicated above. D, Severity of AAA by experimental group (n as indicated in G middle panel). E, Graph showing the survival rate of the experimental groups (Chi-square test). F, Representative hematoxylin-eosin staining of abdominal aortic sections for each experimental group (bars: 200 μm).

Image credit: The authors

Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304222001520-gr1_lrg.jpg

License type: CC BY-NC-ND

Funding information

Instituto de Salud Carlos III (ISCIII) (PI21/01048, PI20/01649),

the European Regional Development Fund (ERDF-FEDER, a way to build Europe),

Ministerio de Ciencia e Innovación (RTI2018-094727-B-100),

AGAUR (2017-SGR-00333, 2017-SGR-1807)

Consejo Superior de Investigaciones Científicas (2021AEP073).

L. P. is supported by a PFIS contract (ISCIII),

C.B–S by a FPU fellowship,

A.R.-S. and M.G. were funded by the Miguel Servet Program.

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