Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: A possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification.

Calcific aortic valve disease (CAVD) is the most frequent pathogeny of aortic valve replacement in developed countries. Iron deposits are found in the intraleaflet hemorrhage (IH) areas of calcific aortic valves. Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron overload-dependent excessive lipid peroxidation. In this study, histological analysis showed that ferroptosis occurs in the IH areas of calcific aortic valves. We also demonstrated that Slc7a11 is expressed at low levels in OM-treated valvular interstitial cells (VICs) and IH areas and that low Slc7a11 expression is associated with calcification in CAVD. However, iron overload treatment did not promote VIC calcification under osteogenic conditions in vitro. Using lentiviral transfection to knockdown Slc7a11 in VICs, we found that the degree of iron overload-induced ferroptosis was positively increased in vitro. Finally, we also found that Slc7a11 knockdown promoted the osteogenic differentiation of VICs in vitro. In summary, this study reports a novel mechanism linking ferroptosis and CAVD development in which iron may promote Slc7a11-deficient VIC osteogenic differentiation by aggravating ferroptosis in vitro, thereby accelerating the progression of aortic valve calcification. Graphical abstract. The graphic illustration of Slc7a11 deficiency facilitates iron overload-induced calcification via exacerbating oxidative stress in VICs. [Display omitted] • Ferroptosis is associated with the progression of calcific aortic valve disease. • Slc7a11 expression is downregulated in osteogenic differentiation valvular interstitial cells (VICs) and calcified aortic valves. • Slc7a11 deficiency aggravates iron overload-induced ferroptosis in vitro. • Iron promotes Slc7a11-deficient VIC osteogenic differentiation by aggravating ferroptosis in vitro. • Tables. [ABSTRACT FROM AUTHOR]