Abstract
Vitamins K exert a range of activities that extend far beyond coagulation and include anti-inflammatory effects, but the mechanisms involved in anti-inflammatory action remain unclear. In the present study, we showed that various forms of exogenous vitamins—K1, K3, K2 (MK-4, MK-5, MK-6 and MK-7)—regulated a wide scope of inflammatory pathways in murine macrophages in vitro, including NOS-2, COX-2, cytokines and MMPs. Moreover, we demonstrated for the first time that macrophages are able to synthesise endogenous MK-4 on their own. Vitamins with shorter isoprenoid chains—K1, K3 and MK-5—exhibited stronger anti-inflammatory potential than vitamins with longer isoprenoid chains (MK-6 and MK-7) and simultaneously were preferably used as a substrate for MK-4 endogenous production. Most interesting, atorvastatin pretreatment inhibited endogenous MK-4 production but had no impact on the anti-inflammatory activity of vitamins K. In summary, our results demonstrate that macrophages are able to synthesise endogenous MK-4 using exogenous vitamins K, and statin inhibits this process. However, the anti-inflammatory effect of exogenous vitamins K was independent of endogenous MK-4 synthesis.
Highlights
Vitamins K was discovered in 1929 as a substance essential for blood coagulation and was named the “coagulation vitamin.” Today, it is well known that “vitamins K” encompasses a group of fat-soluble 2-methyl-1,4 naphthoquinone derivatives with isopropyl side chains, including phylloquinone, menaquinones and menadione [1]
RAW 264.7 cells were stimulated with LPS (1 ng/mL, 24 h) in the presence or absence of various forms of vitamins K (K1, K3, MK-4, MK-5, MK-6 and MK-7) at a concentration of 0, 0.1, 1 and 10 μM added 24 h before LPS stimulation
We characterise the pharmacological effects of a wide range of forms of vitamins K (K1, K3, MK-4, MK-5, MK-6 and MK-7) added exogenously to LPS-stimulated RAW 264.7 cells and demonstrated their anti-inflammatory actions, which included the following: (1) the downregulation of the induction of nitric oxide synthase 2 (NOS-2) and NO production, (2) the downregulation of cyclooxygenase 2 (COX-2) induction and various eicosanoid production (PGE2, PGD2, PGF2α, 11β-PGF2α, 15-deoxy-PGJ2 and 8-isoPGF2α), (3) the inhibition of cytokine production (IL-6 and TNFα) and (4) the inhibition of MMP-2 and MMP-9 expression
Summary
Vitamins K was discovered in 1929 as a substance essential for blood coagulation and was named the “coagulation vitamin.” Today, it is well known that “vitamins K” encompasses a group of fat-soluble 2-methyl-1,4 naphthoquinone derivatives with isopropyl side chains, including phylloquinone (vitamin K1), menaquinones (vitamin K2) and menadione (vitamin K3) [1]. The mechanism of activity of vitamins K is attributed to the reduced form of vitamins K (KH2) that activates blood coagulation factors (prothrombin, factor VII, IX, X) through post-translational modification of vitamins K-dependent proteins (VKDPs) by γ-glutamyl carboxylase (GGCX), which converts glutamate (Glu) residues to γ–carboxyglutamate (Gla). Vitamins K antagonists inhibit coagulation by targeting vitamins K reduction and the warfarin-sensitive enzyme VKOR (vitamins K epoxide reductase) during the “vitamins K cycle” [2]. Vitamins K-dependent mechanisms might play a role in the regulation of coagulation factor synthesis in the liver and in a number of other processes and diseases, such as osteoporosis, osteoarthritis, cancer, diabetes, cognition, vascular calcification [4,5,6,7,8] and inflammation [9,10,11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
