title: Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA. rwallin@wfubmc.edu
authors.forename: Reidar
authors.initials: R
authors.lastname: Wallin
authors.forename: Leon
authors.initials: L
authors.lastname: Schurgers
authors.forename: Nadeem
authors.initials: N
authors.lastname: Wajih
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000166:cytology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002114:Calcinosis / Q000473:pathology* / Q000517:prevention & control*; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D032446:Myoblasts / Q000166:cytology; D010006:Osteoblasts / Q000166:cytology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology*; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000494:pharmacology; D000097568:Matrix Gla Protein
chemical_list: D000933:Antifibrinolytic Agents; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D014812:Vitamin K; D024482:Vitamin K 2; D000097568:Matrix Gla Protein; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C030814:menatetrenone