KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway. Lincoln and colleagues. Circ Res. 2021

Project Description

KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway.

Lincoln and colleagues. Circ Res. 2021

Rationale: Calcific aortic valve disease (CAVD) affects >5.2 million people in the United States. The only effective treatment is surgery, and this comes with complications and no guarantee of long-term success.

Objective: Outcomes from pharmacological initiatives remain unsubstantiated and, therefore, the aim of this study is to determine if repurposing a selective XPO1 (exportin-1) inhibitor drug (KPT-330) is beneficial in the treatment of CAVD.

Methods and Results: We show that KPT-330 prevents, attenuates, and mitigates calcific nodule formation in heart valve interstitial cells in vitro and prevents CAVD in Klotho^−/− mice. Using RNA-sequencing and mass spectrometry, we show that KPT-330’s beneficial effect is mediated by inhibiting nuclear export of the C/EBPβ (transcription factor CCAAT/enhancing-binding protein) in valve interstitial cells, leading to repression of canonical Wnt signaling, in part, through activation of the Wnt antagonist Axin1, and a subsequent decrease in proosteogenic markers and cell viability.

Conclusions: Our findings have met a critical need to discover alternative, pharmacological-based therapies in the treatment of CAVD.

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