REL/STEAP4 promotes aortic valve calcification by inducing iron overload and ferroptosis in valvular interstitial cells.

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 ApoEhigh-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.