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Missense mutation of VKORC1 leads to medial arterial calcification in rats
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Edité par CCSD ; Nature Publishing Group -
International audience. Vitamin K plays a crucial role in the regulation of vascular calcifications by allowing activation of matrix Gla protein. The dietary requirement for vitamin K is low because of an efficient recycling of vitamin K by vitamin K epoxide reductase (VKORC1). However, decreased VKORC1 activity may result in vascular calcification. More than 30 coding mutations of VKORC1 have been described. While these mutations have been suspected of causing anticoagulant resistance, their association with an increase in the risk of vascular calcification has never been considered. We thus investigated functional cardiovascular characteristics in a rat model mutated in VKORC1. This study revealed that limited intake in vitamin K in mutated rat induced massive calcified areas in the media of arteries of lung, aortic arch, kidneys and testis. Development of calcifications could be inhibited by vitamin K supplementation. In calcified areas, inactive Matrix Gla protein expression increased, while corresponding mRNA expression was not modified. Mutation in VKORC1 associated with a limited vitamin K intake is thus a major risk for cardiovascular disease. Our model is the first non-invasive rat model that shows spontaneous medial calcifications and would be useful for studying physiological function of vitamin K. Vascular calcification is a pathology related to age which affects most people over 60 years. It is characterized by deposits of hydroxyapatite crystals in the media and/or intima of the arterial walls. This calcification can lead to complications like high blood pressure or heart failure which are major risk factors for cardiovascular disease. Calcification is accelerated by inflammation, diabetes, chronic kidney disease (CKD), osteoporosis or vitamin K antagonist treatment like warfarin 1. It is widely accepted that vascular calcification is not the consequence of a passive phenomenon but is regulated by complex active mechanisms 1 , especially vitamin K-dependent mechanisms. It has been demonstrated that vitamin K plays a crucial role in the regulation of ectopic calcifications by either holding progression or even reversing vascular calcification 2. Vitamin K is an essential co-factor for the gamma-glutamyl-carboxylase enzyme, which is responsible for activation of 17 vitamin K-dependent proteins (VKDP) by gamma-carboxylation of their glutamate residues. Carboxylation confers these so-called vitamin K-dependent proteins (VKDP) the ability to bind calcium. Among these proteins, factors II, VII, IX and X are involved in the coagulation process. Extrahepatic VKDP such as matrix-Gla-protein (MGP), osteocalcin or Gla-rich protein 3 are involved in bone and calcium metabolism. MGP, when carboxylated, is a potent inhibitor of vascular calcification and knockout of the MGP gene in mice results in premature death by spontaneous cal-cification of arteries 4. Despite the conversion of vitamin K in vitamin K epoxide by the gamma-glutamyl-carboxylase to activate VKDP, the daily requirements for vitamin K in normal adult are low with recommendations for the different countries comprised between 50 to 120 µg/day/adult 5. The low requirement can be explained by an efficient recycling system of vitamin K from vitamin K epoxide by the vitamin K epoxide reductase enzyme (VKORC1) allowing the use of vitamin K for some 500 carboxylation reactions 6. Failure in the reduction of vitamin K epoxide by VKORC1 may result in loss of inhibition of vascular cal-cification and thus may cause accelerated vascular calcification. Reduction in VKORC1 activity results from the daily use of anticoagulant therapy with vitamin K-antagonists to prevent and treat thromboembolic disorders 7. It is now accepted that the long-term use of anticoagulant induces vascular calcification 8-14. Additionally,
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