Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Abstract

In calcific aortic valve disease (CAVD) progressive valvular calcification causes aortic valve dysfunction. CAVD has several risk factors such as age and dyslipidemia. Vitamin K was shown to inhibit vascular calcification in mice and valvular calcification in patients with CAVD. We studied the effect of menaquinone 4 (MK4/vitamin K2) on valvular calcification in the hypercholesterolemic mouse model of CAVD. LDLr−/−ApoB100/100 male mice were fed with a Western diet for 5 months, with (n = 10) or without (n = 10) added 0.2 mg/g MK4. Body weight gain was followed weekly. Morphology of aortic valves and liver was assessed with immunohistochemistry. Plasma cholesterol levels and cytokines from hepatic tissue were assessed in the end of the study. Hepatic gene expression of lipid metabolism regulating genes were assessed after 18 h diet. MK4 exacerbated the lipoprotein lipid profile without affecting aortic valve morphology in hypercholesterolemic LDLr−/− ApoB100/100 mice. The MK4-containing WD diet increased plasma levels of LDL and triglycerides, hepatic steatosis, and mRNA expression of genes required for triglyceride and cholesterol synthesis. MK4 diminished levels of several cytokines and chemokines in liver, including IL-6, TNFα and MCP1, as measured by hepatic cytokine array. Consequently, MK4 may exert non-beneficial effects on circulating lipid levels, especially in hypercholesterolemic individuals.

Lactococcus lactis‑fermented spinach juice suppresses LPS‑induced expression of adhesion molecules and inflammatory cytokines through the NF‑κB pathway in HUVECs

“…These results are not direct evidence that the NF-κB pathway is suppressed by vitamin K 2 to exert a protective effect against vascular inflammation; however, previous data that demonstrated the role of vitamin K 2 in suppressing LPS-induced microglial inflammation ( 36 ), combined with our results, suggest that vitamin K 2 -enriched fermented S.juice may inhibit LPS-induced inflammation by suppressing the NF-κB signaling pathway.…”

“…Kawashima et al ( 35 ) reported anti-atherosclerotic effects in hypercholesterolemic rabbits treated with vitamin K 2 (MK-7; 1 to 10 mg/kg body weight/day) including reduced intimal thickening and ester-cholesterol deposition in the aorta, as well as a slower progression of atherosclerotic plaques. Vitamin K 2 (MK-4) decreased the levels of inflammatory markers such as IL-6, MCP-1, and TNF-α in the liver ( 36 ); this might be attributed to the anti-inflammatory effects of vitamin K 2 . Vitamin K 2 (MK-4; 0.1-10 µM) reduced the levels of IL-6, IL-1β, and TNFα in LPS-induced MG6 mouse microglia-derived cells ( 37 ).…”

The biological responses of vitamin K2: A comprehensive review

“…Thus, VitK2 supplementation has been suggested as a plausible intervention to inhibit the pathogenetic progression of these conditions (Brandenburg et al, 2015 ; Marquis‐Gravel et al, 2016 ). However, in a recent study using a hypercholesterolemic mouse model of calcific aortic valve disease, an MK‐4 diet did not beneficially impact aortic valve morphology but instead increased plasma levels of total cholesterol, triglycerides, and low‐density lipoprotein (Weisell et al, 2021 ).…”

Vitamin K and vascular calcification

“…Although much research has concentrated on the effects of vitamin K-dependent proteins as mediators of the biological effects of vitamin K on vascular calcification, recent findings are a reminder that vitamin K biology is complex and that not all vitamin K dependent pathways inhibit vascular calcification. Administration of the MK-4 vitamin K2 subtype to rodents increased lipid levels in one recent study [26], potentially accelerating atherosclerosis and its associated calcification. In another recent study, MK-4 administration accelerated calcification of aortic valve cells in a high-phosphate environment (hence similar to that found in advanced CKD); this effect was mediated by vitamin K's actions as a nuclear steroid receptor ligand at the pregnane X receptor (the murine counterpart of the steroid and xenobiotic sensing nuclear receptor in humans) [27 ▪ ].…”