Research Paper Advance Articles
Fisetin ameliorates vascular smooth muscle cell calcification via DUSP1-dependent p38 MAPK inhibition
- 1 Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz 4020, Austria
- 2 Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna 1090, Austria
- 3 Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin 13353, Germany
- 4 DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin 13347, Germany
Received: July 30, 2024 Accepted: March 6, 2025 Published: April 2, 2025
https://doi.org/10.18632/aging.206233How to Cite
Copyright: © 2025 Razazian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Medial vascular calcification is highly prevalent in advanced age and chronic kidney disease (CKD), where it is associated with increased risk for cardiovascular events and mortality. Vascular smooth muscle cells (VSMCs) actively regulate this process, which can be augmented by inflammation and cellular senescence. Thus, the present study investigated the impact of fisetin, a flavonol with anti-inflammatory and senolytic properties, on VSMC calcification. Fisetin treatment suppressed calcific marker expression and calcification of VSMCs as well as p38 MAPK phosphorylation induced by pro-calcific conditions. These effects were abolished by silencing of dual-specificity phosphatase 1 (DUSP1), a negative regulator of p38 MAPK activity. Moreover, knockdown of DUSP1 alone was sufficient to increase calcific marker expression in VSMCs, effects blunted by pharmacological p38 MAPK inhibition. Accordingly, DUSP1 knockdown aggravated calcification of VSMCs during pro-calcific conditions. In addition, fisetin ameliorated the effects of uremic conditions in VSMCs exposed to serum from dialysis patients. Fisetin also inhibited vascular calcification as well as calcific marker expression ex vivo in mouse aortic explants exposed to high phosphate and in vivo in a cholecalciferol overload mouse model. In conclusion, fisetin acts as a potent anti-calcific agent during VSMC calcification, an effect involving DUSP1-mediated regulation of p38 MAPK-dependent pro-calcific signaling.