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Updated: Jan 14, 2026
Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
Published on: May 10, 2021
REL/STEAP4 promotes aortic valve calcification by inducing iron overload and ferroptosis in valvular interstitial
Ruikang Guo1, Bingchuan Geng1, Wai Yen Yim1
1Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, 430022, China.
Insights
Iron overload and ferroptosis drive calcific aortic valve disease (CAVD) progression. Inhibiting ferroptosis and targeting the REL/STEAP4 pathway offers a promising new therapy for CAVD.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Pathogenesis of Cardiovascular Diseases
Background:
- Ferroptosis is implicated in cardiovascular diseases, but its role in calcific aortic valve disease (CAVD) is poorly understood.
- Iron overload is increasingly recognized as a factor in cardiovascular pathology.
Purpose of the Study:
- To investigate the role of iron overload and ferroptosis in the pathogenesis of CAVD.
- To identify molecular targets for potential therapeutic intervention in CAVD.
Main Methods:
- Utilized in vitro cell culture models (human valve interstitial cells) and in vivo mouse models (ApoE-/- high-fat diet, wire-injury induced CAVD).
- Performed transcriptomic analysis and cellular experiments to identify key molecular players.
- Assessed the efficacy of ferroptosis inhibitors in mitigating CAVD progression.
Main Results:
- Established a direct association between iron overload, ferroptosis, and calcification in CAVD models.
- Ferroptosis inhibitors significantly reduced CAVD progression both in vitro and in vivo.
- Identified STEAP4 as a key mediator of iron overload and ferroptosis in calcifying valve cells.
- Discovered that REL (NF-κB subunit) enhances STEAP4 expression via promoter binding.
Conclusions:
- The REL/STEAP4 axis is crucial for orchestrating iron overload and ferroptosis in CAVD.
- Targeting the REL/STEAP4 pathway presents a novel therapeutic strategy for treating CAVD.
Abstract:
Ferroptosis has been recognized to be pivotal in the pathogenesis of various cardiovascular diseases, yet with poor understanding regarding its involvement in calcific aortic valve disease (CAVD). This study established a connection between iron overload and ferroptosis in CAVD, demonstrating their association with calcification in both aortic valves and human valve interstitial cells (hVICs) cultured in a calcifying medium. An ApoE-/- high-fat diet mouse model and a wire-injury-induced model of CAVD were also employed to examine the in vivo contribution of ferroptosis to valvular calcification. Notably, the application of ferroptosis inhibitors effectively mitigated the progression of CAVD in vitro and in vivo. Furthermore, STEAP4 was found to be the primary contributor to iron overload and induction of ferroptosis in calcifying hVICs through a comprehensive analysis of transcriptomes and in vitro cellular experiments. Our investigation also unveiled that REL, a subunit of NF-κB, could enhance STEAP4 expression by binding to its promoter. In summary, targeting the REL/STEAP4 axis, responsible for orchestrating iron overload and ferroptosis, holds promise as a novel therapeutic solution for CAVD.
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