TGF-β and Wnt Pathways Underlying the Pathophysiology of Degenerative Mitral Valve Regurgitation

Abstract

Objectives: In aging society, hospitalizations and mitral valve surgeries are becoming more common due to progressive mitral valve diseases that ultimately lead to heart failure. In developing countries, degenerative mitral valve regurgitation (DMVR) is the leading cause of mitral regurgitation requiring surgical treatment. Nevertheless, a more profound understanding of the underlying pathological processes via a molecular biology approach could improve clinical management. In this study, bioinformatic analyses were performed to elucidate the underlying pathophysiological molecular mechanisms using transcriptome data of atrial tissues from patients with DMVR. Materials and Methods: Bioinformatic analysis were done using GSE115574 dataset from The Gene Expression Omnibus (GEO) database. Transcriptome data which were downloaded from GEO database in CEL files generated from human left atrium and right atrium tissues in patients with DMVR in sinus rhythm (n=16) was used to perform bioinformatic analysis. Gene expression microarray analysis have done on Affymetrix platform previously. Bioinformatics, gene ontology, and functional enrichment analysis have been conducted on Partek GS V7.0 and WebGestalt software. Results: The findings of this study reveal that multiple genes and various pathways play a role in the pathophysiology of DMVR. Among all transforming growth factor-beta (TGF-β) and Wnt signaling pathways enlightened according to false discovery rate thresholds and enriched geneset values. Prominent genes that involved in TGF-β and Wnt signaling pathways were WNT5A, PLCB1, SFRP1, SMAD6, PITX2, SMAD7, ID2, BMP5. Conclusion: It’s important to crystallize the molecular mechanisms of DMVR to facilitate early detection and develop targeted interventions. Management of TGF-β and Wnt signaling pathways in correct direction may offer solutions to slow DMVR progression and prevent it from becoming more complex.

Keywords

• Mitral valve
• TGF-β signaling pathway
• Wnt signaling pathway

Dejeneratif Mitral Yetmezliği Patofizyolojisinde Yer Alan TGF-β ve Wnt Sinyal Yolakları

Abstract

Amaç: Yaşlanan toplumlarda, en nihayetinde kalp yetmezliğine ilerleyen progresif mitral kapak hastalıkları nedeniyle hastaneye yatışlar ve mitral kapak ameliyatları daha yaygın hale gelmiştir. Gelişmekte olan ülkelerde, dejeneratif mitral kapak yetersizliği (DMVR) cerrahi tedavi gerektiren mitral yetersizliğinin önde gelen nedenidir. Bununla birlikte, altta yatan patolojik süreçlerin moleküler biyoloji yaklaşımıyla daha derinlemesine anlaşılması klinik yönetimi iyileştirebilir. Bu araştırmada, DMVR’li hastalardan alınan atriyum dokularının transkriptom verisi kullanılarak, altta yatan patofizyolojik moleküler mekanizmaları aydınlatmak amacıyla biyoinformatik analizler yapılmıştır. Gereç ve Yöntem: Biyoinformatik analizler, Gen Ekspresyon Omnibus (GEO) veritabanından GSE115574 veriseti kullanılarak gerçekleştirilmiştir. Sinüs ritmindeki DMVR hastalarında (n=16) insan sol atriyum ve sağ atriyum elde edilen ve GEO veritabanından CEL dosyaları olarak indirilen transkriptom verisi biyoinformatik analizleri yapmak için kullanılmıştır. Gen ekspresyon mikroarray analizleri daha öncesinde Affymetrix platformunda gerçekleştirilmiştir. Biyoinformatik, gen ontolojisi ve fonksiyonel zenginleştirme analizleri Partek GS V7.0 ve WebGestalt yazılımlarında gerçekleştirilmiştir. Bulgular: Bu çalışmanın bulguları, DMVR patofizyolojisinde birden fazla genin ve çeşitli yolakların rol oynadığını ortaya koymaktadır. Tüm dönüştürücü büyüme faktörü-beta (TGF-β) ve Wnt sinyal yolakları arasında yanlış keşif oranı eşiklerine ve zenginleştirilmiş gen seti değerlerine göre aydınlatılmıştır. TGF-β ve Wnt sinyal yolaklarında yer alan öne çıkan genler WNT5A, PLCB1, SFRP1, SMAD6, PITX2, SMAD7, ID2, BMP5 olarak tespit edilmiştir. Sonuç: Erken teşhisi kolaylaştırmak ve hedefe yönelik müdahaleler geliştirmek için DMVR’nin moleküler mekanizmalarının tam olarak aydınlatılması önemlidir. TGF-β ve Wnt sinyal yolaklarının doğru şekilde yönetilmesi, DMVR progresyonunu yavaşlatmak ve daha karmaşık hale gelmesini önlemek için çözümler sunabilir.

Keywords

• Mitral kapak
• TGF-β sinyal yolağı
• Wnt sinyal yolağı

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