Vitamin K-dependent proteins, warfarin, and vascular calcification.
Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.
Danziger
John
J
Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. jdanzige@bidmc.harvard.edu
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002114:Calcinosis / Q000139:chemically induced* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018570:Risk Assessment; D012307:Risk Factors; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism*; D014859:Warfarin / Q000009:adverse effects*; D000097568:Matrix Gla Protein; D000099255:Growth Arrest-Specific Protein 6
D000925:Anticoagulants; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014812:Vitamin K; D014859:Warfarin; D000097568:Matrix Gla Protein; D000099255:Growth Arrest-Specific Protein 6