The Role of Wnt/β-Catenin Pathway Mediators in Aortic Valve Stenosis.

Kashif Khan,Megan Cipro,Dominique Shum-Tim,Renzo Cecere,Chrystina Kiwan,Yousif Shalal,Sabin Filimon,Adel Schwertani,Bin Yu

doi:10.3389/fcell.2020.00862

Kashif Khan, Megan Cipro + Show 7 more

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https://doi.org/10.3389/fcell.2020.00862

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Abstract

Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β-catenin pathway mediators, SFRP2, DVL2, GSK3β and β-catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real-Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK-3β, DVL2, and β-catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK-3β, DVL2, β-catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b, and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.

Highlights

Aortic valve stenosis (AVS) is a prevailing cause of cardiac debility and death, affecting 2.8% of adults ≥75 years of age (Benjamin et al, 2011)
The mRNA expression of DVL1 and DVL2 were significantly increased in stenotic valves compared to healthy valves, with no differences found for DVL3 (Figure 1)
Our lab has previously demonstrated that several non-canonical Wnt ligands are present in AVS patients and promote calcification and apoptosis in human aortic valve interstitial cells (HAVICs) (Albanese et al, 2017)

Summary

Introduction

Aortic valve stenosis (AVS) is a prevailing cause of cardiac debility and death, affecting 2.8% of adults ≥75 years of age (Benjamin et al, 2011). It is associated with multiple risk factors such as hypertension, lack of exercise, hypercholesterolemia, diabetes and elevated plasma Lp(a) (Lindman et al, 2016). Therapies for AVS patients are limited to valve replacement surgery, with no treatment available to reverse the effects of the disease (James Everett et al, 2018). Examining the molecular signalling involved in the pathogenesis of AVS will aid in identifying more treatment modalities for this perilous disease.

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