https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Universitätsklinikum Bonn Institut für Experimentelle Hämatologie und Transfusionsmedizin Bonn, Deutschland; 3Kreiskrankenhaus Waldbröl GmbH Klinik für Innere Medizin, Kardiologie Waldbröl, Deutschland
Background:
Vitamin K exerts anti-oxidative properties which were proposed to be mediated by the vitamin K cycle enzyme VKORC1L1 (vitamin-K-2,3-epoxide-reductase-complex-subunit-1-like-1). Anti-oxidative mechanisms are critical for proper endothelial function and to ensure regeneration of the endothelium upon injury. Here, we investigated the role of vitamin K on endothelial cell regeneration and anti-oxidation.
Methods and Results:
In human coronary artery endothelial cells (HCAEC), treatment with the vitamin K2 vitamer MK-7 (Menaquinone-7) promoted a regenerative endothelial phenotype by increasing cell viability and proliferation while reducing apoptosis and ferroptosis. Moreover, MK-7 enhanced anti-oxidative capacityby inhibiting lipid peroxidation, reactive oxygen species (ROS) formation, endothelial-to-mesenchymal transition, and activation of NF-κB/ICAM-1 signaling. Knockdown experiments using RNA interference revealed that loss of VKORC1L1, but not of canonical VKORC1, leads to increased oxidative stress and inflammation. Importantly, MK-7 required VKORC1L1, but not VKORC1, to exert its protective effects on lipid peroxidation and ROS formation. RNA sequencing showed that VKORC1L1silencing upregulated tumor necrosis factor (TNF). Inhibition of TNF shedding abolished ROS formation and inflammation in VKORC1L1-silenced HCAEC.
Conclusion:
Vitamin K promotes regeneration in endothelial cells by alleviating oxidative stress, lipid peroxidation, and cell death by ferroptosis. These effects were mediated by VKORC1L1 but not by the canonical vitamin K cycle enzyme VKORC1.