Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Abstract

Arterial calcification (AC) is generally regarded as an independent risk factor for cardiovascular morbidity and mortality. Matrix Gla protein (MGP) is a potent inhibitor of AC, and its activity depends on vitamin K (VK). In rats, inactivation of MGP by treatment with the vitamin K antagonist warfarin leads to rapid calcification of the arteries. Here, we investigated whether preformed AC can be regressed by a VK-rich diet. Rats received a calcification-inducing diet containing both VK and warfarin (W&K). During a second 6-week period, animals were randomly assigned to receive either W&K (3.0 mg/g and 1.5 mg/g, subsequently), a diet containing a normal (5 g/g) or high (100 g/g) amount of VK (either K 1 or K 2 ). Increased aortic calcium concentration was observed in the group that continued to receive W&K and also in the group changed to the normal dose of VK and AC progressed. Both the VK-rich diets decreased the arterial calcium content by some 50%. In addition, arterial distensibility was restored by the VK-rich diet. Using MGP antibodies, local VK deficiency was demonstrated at sites of calcification. This is the first study in rats demonstrating that AC and the resulting decreased arterial distensibility are reversible by high-VK intake. IntroductionArterial calcification is an important independent risk factor for the development of atherosclerosis, myocardial infarction, stroke, and renal disease. 1,2 Patients with manifest arterial calcification have an unfavorable prognosis compared with patients with no or mild calcification. 3,4 Therefore, the prevention or reversal of arterial calcification may lead to improved patient outcomes.For a long time it has been thought that calcification was a passive process and the end stage of cardiovascular disease. During the past 10 years, however, it has become clear that several osteoregulatory proteins, both stimulatory and inhibitory, are involved in the calcification of vascular tissue. [5][6][7][8] One of the strongest in vivo inhibitors of arterial calcification is matrix Gla protein (MGP). MGP was first discovered in bone, 9 but it is mainly produced by vascular smooth muscle cells and chondrocytes. Its function became clear in MGP-deficient mice, 10 which died within 6 to 8 weeks after birth as a result of rupture of the large arteries. Histochemical evaluation demonstrated complete calcification of the elastic fibers in the arterial vessels and a phenotypic change of smooth muscle cells into chondrocytes. MGP acts by direct inhibition of calcium crystal formation and regulates bone morphogenetic protein-2, a growth factor responsible for osteogenic differentiation. [11][12][13] Murshed et al 14 demonstrated that restoration of MGP exclusively in the vascular smooth muscle cells of the MGP-null mice completely rescued the vascular calcification phenotype. For this effect the MGP needed to be ␥-carboxylated because mutating the Gla residues into aspartic acid residues led to the synthesis of nonfunctional MGP and to the death of all animals.Vitamin K is an e...

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

“…The effects of vitamin K were not consistent or dose-dependent, reaching at most a 30% (not statistically significant) reduction in calcification with the remaining calcium levels being still seven times higher than in the control cells. This limited efficiency of vitamin K in vitro is in agreement with a 50% reduction of arterial calcification observed in the rat model of warfarin-induced elastocalcinosis supplemented with high dose of vitamin K2 (48). Altogether, these observations indicate that although ablation of GlaMGP probably contributes to the effects of high warfarin concentrations on vascular cells, the role for this mechanism in clinically relevant warfarin-induced VC is relatively minor.…”

Does the absence of ABCC6 (Multidrug Resistance Protein 6) in patients withPseudoxanthoma elasticumprevent the liver from providing sufficient vitamin K to the periphery?

“…Non-carboxylated MGP (ucMGP) is inactive in preventing the calcification. [22][23][24] MGP-deficient KO mice manifest extensive calcification of the aorta and of the articular cartilage and they die at an early age. 25 The carboxylation step in the vascular smooth muscle cells can become rate-limiting if the vitamin K supply is inadequate.…”

VKORC1L1, an Enzyme Rescuing the Vitamin K 2,3-Epoxide Reductase Activity in Some Extrahepatic Tissues during Anticoagulation Therapy

“…Warfarin Resistance of Extrahepatic Tissues May Be Explained by VKORC1L1-During long term anticoagulation therapy, effects on VKDPs involved in coagulation process are observed whereas effects on VKDPs produced in extrahepatic tissues are not apparent or quite difficult to observe. Indeed, to induce arterial calcification by warfarin in rats, excessive doses of anticoagulants widely superior to the therapeutic doses were used in the various studies previously published (20,32,33). Price et al (33) had to treat rats twice a day with 150 mg/kg warfarin (ϳ4000-fold higher than the therapeutic dose used in human medicine) to induce rapid calcification of the elastic lamellae in the media of major arteries and in aortic heart valves.…”