ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. Atherosclerosis and Vascular Medicine
Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1586775
This article is part of the Research TopicCardiovascular calcification: disease mechanisms, clinical phenotypes and therapeutic strategiesView all 5 articles
Nutrient restriction protects against valve interstitial cell calcification by upregulating ubiquitin mediated proteolysis
Provisionally accepted
- 1University of Edinburgh, Edinburgh, United Kingdom
- 2Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom
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Calcific aortic valve disease (CAVD) is a prevalent valvular heart disease driven by the pathological calcification of valve interstitial cells (VICs). Current therapeutic options, including valve replacement and transcatheter implantation, are invasive and fail to address the underlying calcific mechanisms. In this study, we investigate the potential of nutrient restriction (NR) to mitigate calcification in VICs, focusing on the role of the ubiquitin-proteasome system (UPS). Rat valvular interstitial cells (RVICs) were subjected to in vitro calcification using calcium-and phosphateenriched media, with NR induced by Hank's Balanced Salt Solution (HBSS). NR significantly downregulated osteogenic markers and decreased calcium deposition.Proteomic analysis using stable isotope labeling by amino acids in cell culture (SILAC) revealed the upregulation of the UPS in nutrient-deprived RVICs. Key components of the UPS, including Cullin-2 (Cul2) and Ubiquitin-conjugating enzyme E2 H (Ube2H), were identified as potential mediators of the observed anticalcification effects. Pharmacological inhibition of the 20S proteasome using MG132 exacerbated calcification, further highlighting the protective role of Ubiquitin proteosome pathway. Additionally, siRNA-mediated knockdown of Cul2 increased osteogenic marker expression and calcification, underscoring its essential role in mitigating calcification under nutrient-restricted conditions. This study highlights NR as a promising non-invasive intervention for preventing VIC calcification by modulating the UPS. Targeting the UPS components or employing dietary interventions may offer novel therapeutic strategies for managing CAVD.
Keywords: Nutrient restriction, Calcific aortic valve disease, Ubiquitin mediated proteolysis, Cullin-2, SILAC
Received: 03 Mar 2025; Accepted: 04 Jul 2025.
Copyright: © 2025 Phadwal, Tang, Kurian, Tan, Cawthorn and MacRae. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qiyu Tang, University of Edinburgh, Edinburgh, United Kingdom
Vicky E MacRae, University of Edinburgh, Edinburgh, United Kingdom
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