title: Decreased expression of γ-carboxylase in diabetes-associated arterial stiffness: impact on matrix Gla protein.
abstract: OBJECTIVE
  Arterial stiffness is accelerated in type 1 diabetic patients. Medial artery calcification (MAC) contributes to the development of arterial stiffness. Vitamin K oxidoreductase (VKOR) reduces the vitamin K required by γ-carboxylase to activate matrix γ-carboxyglutamic acid (Gla) protein (MGP), an inhibitor of vascular calcification. This study aimed to evaluate the hypothesis that diabetes reduces the γ-carboxylation of MGP in the aortic wall, leading to increased vascular calcification, and the role of γ-carboxylase and VKOR in this γ-carboxylation deficit.
  
  
  RESULTS
  Type 1 diabetes was induced in male Wistar rats with a single ip injection of streptozotocin. Augmentation of arterial stiffness in diabetic rats was shown by a 44% increase in aortic pulse wave velocity. Aortic and femoral calcification were increased by 26 and 56%, respectively. γ-Carboxylated MGP (cMGP, active) was reduced by 36% and the aortic expression of γ-carboxylase was reduced by 58%. Expression of γ-carboxylase correlated with cMGP (r= 0.59) and aortic calcification (r = -0.57). VKOR aortic expression and activity were not modified by diabetes. Vitamin K plasma concentrations were increased by 191% in diabetic rats. In ex vivo experiments with aortic rings, vitamin K supplementation prevented the glucose-induced decrease in γ-carboxylase expression.
  
  
  CONCLUSIONS
  Our results suggest that reduced cMGP, through an impaired expression of γ-carboxylase, is involved in the early development of MAC in diabetes, and therefore, in the acceleration of arterial stiffness. A defect in vitamin K uptake by target cells could also be involved.
authors.affiliation: Faculty of Pharmacy, Université de Montréal, 2900 Édouard-Montpetit, Room 2143, P.O. Box 6128, Station Centre-Ville, Montréal, Québec H3C 3J7, Canada.
authors.forename: Marielle
authors.initials: M
authors.lastname: Doyon
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
authors.forename: Pierre
authors.initials: P
authors.lastname: Moreau
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D019735:Carbon-Carbon Ligases / Q000502:physiology*; D053298:Chylomicron Remnants / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone); D015675:Osteocalcin / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D061205:Vascular Calcification / Q000209:etiology*; D059289:Vascular Stiffness; D014812:Vitamin K / Q000097:blood; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D019735:Carbon-Carbon Ligases; D053298:Chylomicron Remnants; D016326:Extracellular Matrix Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D015675:Osteocalcin; D013311:Streptozocin; D014812:Vitamin K; D000097568:Matrix Gla Protein; C020660:glutamyl carboxylase