WARFARIN CAUSES RAPID CALCIFICATION OF THE ELASTIC LAMELLAE IN RAT ARTERIES AND HEART-VALVES

High doses of warfarin cause focal calcification of the elastic lamell ae in the media of major arteries and in aortic heart valves in the ra t. Aortic calcification was first seen after 2 weeks of warfarin treat ment and progressively increased in density at 3, 4, and 5 weeks of tr eatment. By 5 weeks, the highly focal calcification of major arteries could be seen on radiographs and by visual inspection of the artery. T he calcification of arteries induced by warfarin is similar to that se en in the matrix Gla protein (MGP)-deficient mouse, which suggests tha t warfarin induces artery calcification by inhibiting gamma-carboxylat ion of MGP and thereby inactivating the putative calcification-inhibit ory activity of the protein. Warfarin treatment markedly increased the levels of MGP mRNA and protein in calcifying arteries and decreased t he level of MCP in serum. Warfarin treatment did not affect bone growt h, overall weight gain, or serum calcium and phosphorus levels, and, b ecause of the concurrent administration of vitamin K, prothrombin time s and hematocrits were normal. The results indicate that the improved warfarin plus vitamin K treatment protocol developed in this study sho uld provide a useful model to investigate the role of MGP in preventin g calcification of arteries and heart valves.