Matrix gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells - A cell system which resembles the system in bone cells

Matrix GLA protein (MGP) is an inhibitor of calcification in the arterial w all and its activity is dependent upon vitamin K-dependent gamma-carboxylat ion. This modification is carried out by a warfarin sensitive enzyme system that converts specific Glu residues to gamma-carboxyglutamic acid (GLA) re sidues. Recent studies have demonstrated that the gamma-carboxylation syste m in the arterial wail, in contrast to that In the liver, is unable to use vitamin K as an antidote to warfarin. By use of immunohistochemistry we demonstrate that MGP is expressed in the arterial wall and immunocytochemistry localized the MGP precursors to the e ndoplasmic reticulum in vascular smooth muscle cells. Resting smooth vascul ar muscle cells in the aortic wall and proliferating cells from explants of the aorta have all the enzymes needed for gamma-carboxylation of MGP. Howe ver, when compared to the: liver system, expression of the enzymes of the g amma-carboxylation system in vascular smooth muscle cells is different. Of particular interest is the finding that the specific activity of the warfar in sensitive enzyme vitamin K epoxide reductase is 3-fold higher in vascula r smooth muscle cells than in liver. DT-diaphorase, which catalyses the ant idotal pathway for vitamin K reduction in liver, is 100-fold less active in resting vascular smooth muscle cells than in liver. Data obtained from an in vitro gamma-carboxylation system suggest that the antidotal pathway cata lyzed by DT-diaphorase in the vessel wall is unable to provide the carboxyl ase with enough reduced vitamin K to trigger gamma-carboxylation of MGP. Th is finding provides an explanation to the inability of vitamin K to work as an antidote to warfarin intoxication of the arterial wall. Therefore the v itamin K dependent gamma-carboxylation system in the arterial wail share a common feature with the system in bone cells by being unable to utilize vit amin K as an antidote.