The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification

Abstract

Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases

“…Ample evidence has shown that VK deficiency is related to the pathogenesis of VC [81][82][83][84]. VK has been suggested to inhibit VC and protect against cardiovascular disease (CVD) through the activation of VKDPs, such as MGP.…”

“…VC, a hallmark of senescence and a strong predictor of CV events, is another chronic inflammatory state induced via the generation of proinflammatory cytokines and mediated by the NF-кB signaling pathway. A high VK status may exert anti-inflammatory effects and prevent VC through antagonizing NF-кB signaling [83]. Growing evidence shows that VK as well as nuclear factor erythroid 2-related factor 2 (Nrf2) signaling could play a vital role in blocking ROS generation, cellular senescence, DNA damage, and inflammaging [84].…”

Effects of vitamin K2 supplementation on atherogenic status of individuals with type 2 diabetes: a randomized controlled trial

“…The most well-known VKDP produced by smooth muscle cells is MGP that inhibits vascular calcification. A higher circulatory level of dp-ucMPG, the best vitamin K insufficiency marker, has been related to a higher risk of vascular calcification, cardiovascular events, and CVD mortality [ 10 , 23 ]. The anti-inflammatory effects of vitamin K also increase the possibility of its contribution to cardiovascular health [ 10 , 22 ].…”

“…A higher circulatory level of dp-ucMPG, the best vitamin K insufficiency marker, has been related to a higher risk of vascular calcification, cardiovascular events, and CVD mortality [ 10 , 23 ]. The anti-inflammatory effects of vitamin K also increase the possibility of its contribution to cardiovascular health [ 10 , 22 ]. Higher intakes of dietary vitamin K have been associated with the lower risk of total coronary heart disease based on the pooled data from prospective studies on associations between dietary intakes of vitamin K1 ( n = 4) and K2 ( n = 2) and cardiovascular events.…”

“…Gamma carboxylation of Matrix Gla protein (MGP), a vitamin K-dependent protein, inhibits vascular mineralization. Of three forms of MGP identified in blood, dephosphorylated-uncarboxylated MGP (dp-ucMGP), a biomarker for vitamin K deficiency, was positively associated with vascular calcification, CVD events, and mortality [ 10 ]. However, a systematic review of the effects of vitamin K supplementation on clinical measures of vascular calcification, atherosclerosis, and arterial stiffness, reported that while the supplementation can decrease the levels of dp-ucMGP, the beneficial effects of vitamin K on reducing the risk of CVD is uncertain, according to the results of the current studies.…”