Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification

Thromb Res. 2008;122(3):411-7. doi: 10.1016/j.thromres.2007.12.005. Epub 2008 Jan 30.


Introduction: The transformation of smooth muscle cells (VSMCs) in the vessel wall to osteoblast like cells is known to precede arterial calcification which may cause bleeding complications. The vitamin K-dependent protein MGP has been identified as an inhibitor of this process by binding BMP-2, a growth factor known to trigger the transformation. In this study, we determined if the vitamin K-dependent Gla region in MGP by itself can inhibit the growth factor activity of BMP-2 and if menaquinone-4 (MK4) regulates gene expression in VSMCs.

Materials and methods: A synthetic gamma-carboxyglutamic acid (Gla) containing peptide covering the Gla region in human MGP was used to test its ability to inhibit BMP-2 induced transformation of mouse pro-myoblast C2C12 cells into osteoblasts. MK4 was tested by microarray analysis as a gene regulatory molecule in VSMCs.

Results and conclusions: The results show that the Gla - but not the Glu-peptide inhibited the transformation which provide evidence that the Gla region in MGP is directly involved in the BMP-2/MGP interaction and emphasizes the importance of the vitamin K-dependent modification of MGP. From the data obtained from the microarray analysis, we focused on two quantitatively altered cDNAs representing proteins known to be associated with vessel wall calcification. DT-diaphorase of the vitamin K-cycle, showed increased gene expression with a 4.8-fold higher specific activity in MK4 treated cells. Osteoprotegrin gene expression was down regulated and osteoprotegrin protein secretion from the MK4 treated cells was lowered to 1.8-fold. These findings suggest that MK4 acts as an anti-calcification component in the vessel wall.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antifibrinolytic Agents / pharmacology*
  • Aorta, Thoracic / cytology
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / metabolism
  • Calcinosis / pathology*
  • Calcinosis / prevention & control*
  • Calcium-Binding Proteins / pharmacology
  • Cell Differentiation / drug effects
  • Cell Line
  • Extracellular Matrix Proteins / pharmacology
  • Humans
  • Mice
  • Muscle, Smooth, Vascular / cytology*
  • Muscle, Smooth, Vascular / drug effects*
  • Myoblasts / cytology
  • Osteoblasts / cytology
  • Peptide Fragments / pharmacology
  • Rats
  • Transforming Growth Factor beta / metabolism
  • Vitamin K / pharmacology*
  • Vitamin K 2 / analogs & derivatives
  • Vitamin K 2 / pharmacology


  • Antifibrinolytic Agents
  • BMP2 protein, human
  • Bmp2 protein, mouse
  • Bmp2 protein, rat
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • Peptide Fragments
  • Transforming Growth Factor beta
  • matrix Gla protein
  • Vitamin K 2
  • Vitamin K
  • menatetrenone