Menaquinone-4 inhibits the formation and vulnerability of atherosclerotic plaques in apolipoprotein E knockout mice by decreasing the uptake of the oxidized low-density lipoprotein in macrophages.

Menaquinone-4 (MK-4), a subtype of vitamin K2 (VK2), is associated with bone metabolism, blood coagulation and anti-inflammation. Atherosclerosis develops and progresses as oxidized low-density lipoprotein (oxLDL) uptake in macrophages via scavenger receptors, leading to the formation of foam cells and vulnerable plaques. However, the effects of MK-4 on macrophages in atherosclerosis and on oxLDL uptake in macrophages remain unclear. This study investigated the effects of MK-4 on atherosclerotic plaque formation and vulnerability, focusing on macrophage function and plaque stability. In apolipoprotein E (ApoE) knockout (KO) mice, oral MK-4 (15 mg/kg/day) significantly inhibited atherosclerotic plaque formation in the aorta. MK-4 also stabilized plaques by reducing foam cell accumulation and preventing fibrous cap disruption without altering plasma cholesterol levels. In vitro, MK-4 (0-30 μM) dose-dependently suppressed oxLDL uptake in macrophages, a key factor in foam cell formation. Additionally, MK-4 (30 μM) significantly reduced the lipopolysaccharide (LPS)-induced expression of scavenger receptors (SR-A and CD36) and proinflammatory cytokines (TNF-α and OPN), as well as blocked the activation of MAP kinases (p38, JNK, and ERK) caused by LPS stimulation. Notably, JNK inhibition played a central role in reducing the expression of inflammatory markers and scavenger receptors. In conclusion, MK-4 suppresses foam cell formation and inflammation by blocking MAP kinase signaling in macrophages, thereby preventing the progression and destabilization of atherosclerotic plaques. These findings suggest that MK-4 may be useful for preventing the onset of cardiovascular diseases, such as myocardial infarction and unstable angina.