KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway
- 19 February 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 128 (9), 1300-1316
- https://doi.org/10.1161/circresaha.120.318503
Abstract
Rationale: Calcific Aortic Valve Disease (CAVD) affects more than 5.2 million people in the US. 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 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 (VICs) 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 transcription factor C/EBPβ in VICs, leading to repression of canonical Wnt signaling, in part through activation of the Wnt antagonist Axin1, and a subsequent decrease in pro-osteogenic markers and cell viability. Conclusions: Our findings have met a critical need to discover alterative, pharmacological-based therapies in the treatment of CAVD.Keywords
Funding Information
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL132801)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL142685)
- American Heart Association (18POST33990408)
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