vitamin-k-semiquinone-radical and Aortic-Diseases

Peripheral arterial occlusive disease is one manifestation of the systemic disease atherosclerosis. The initial therapy for every arteriosclerotic disease is aimed at reducing cardiovascular risk factors by lifestyle modification and medication. Patients who require surgical revascularisation need long-term antiplatelet therapy or anticoagulation. This therapy has to be differentiated according to the vascular territory involved and the method used for revascularisation. After local thrombendarterectomy, alloplastic bypass graft surgery of the aortic, aorto-iliac, aorto-femoral or femoro-popliteal region above the knee, long-term ASA 100 mg/d or clopidogrel 75 mg/d should be initiated. After alloplastic bypass grafting below the knee the combination of ASA 100 mg/d and clopidogrel 75 mg/d should be used. In contrast, after venous grafts the patency rate is improved by anticoagulation with vitamin K antagonists (INR 2-3), if there is a low risk of bleeding. If there is a contraindication to vitamin K antagonists, ASA 100 mg/d should be used. After revascularisation, a structured surveillance programme should be implemented aiming at controlling cardiovascular risk factors and monitoring the vascular state, as well as the anticoagulation and the antiplatelet therapy.

Topics: Aortic Diseases; Aspirin; Blood Vessel Prosthesis Implantation; Clopidogrel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endarterectomy; Evidence-Based Medicine; Femoral Artery; Fibrinolytic Agents; Follow-Up Studies; Humans; Iliac Artery; International Normalized Ratio; Peripheral Arterial Disease; Polyethylene Terephthalates; Polytetrafluoroethylene; Popliteal Artery; Postoperative Complications; Prosthesis Design; Ticlopidine; Veins; Vitamin K

The vitamin K-dependent protein, matrix Gla protein (MGP) is a binding protein for bone morphogenetic protein-2 (BMP-2). Here we present additional evidence that the Ca2+-induced conformer of the vitamin K-dependent Gla region in MGP is involved in BMP-2 binding. Recombinant BMP-2 binds to the Gla-containing region of MGP in the presence of Ca2+. Immunohistochemistry showed that calcified lesions in the aortic wall of aging rats contained elevated concentrations of MGP that was poorly gamma-carboxylated and did not bind BMP-2. In contrast, we were able to identify glandular structures in the mucosa of the rat nasal septum that gave bright fluorescent signals with both antigens; confocal microscopy confirmed their colocalization. These results demonstrate that the BMP-2/MGP complex exists in vivo, consistent with a role for MGP as a BMP-2 inhibitor. Age-related arterial calcification may be a consequence of under-gamma-carboxylation of MGP, allowing unopposed BMP-2 activity.

Topics: Amino Acid Sequence; Animals; Aortic Diseases; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Calcium; Calcium-Binding Proteins; Cattle; Extracellular Matrix Proteins; Female; Fluorescent Antibody Technique; Growth Hormone; Humans; Immunohistochemistry; Matrix Gla Protein; Microscopy, Confocal; Molecular Sequence Data; Nasal Mucosa; Nasal Septum; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Transforming Growth Factor beta; Vitamin K

To investigate the relationship among lipids, coagulation and thrombosis in the absence of atherosclerosis, spontaneous or dietary-induced hyperlipidemic (FHL) rats were studied. FHL showed higher levels of coagulation factors VII, IX, X, VIII and XII and a shortening of the occlusion time (OT) of an artificial arterial prosthesis as compared with normolipidemic (FNL) animals. Damage of abdominal aorta of FHL was followed by increased fibrin deposition in the vascular intima as compared to FNL. After 5 months of cholesterol-rich diet FNL showed increased cholesterol, triglycerides and factor II, VII, IX, X, XII levels. A significant shortening of the OT and increased fibrin deposition was also observed. Two-month diet withdrawal restored the initial condition. Warfarin treatment, at a dose decreasing vitamin K-dependent factor to levels found in FNL, prolonged the OT and reduced fibrin deposition, without modifying F XII or changing lipid profile. An increase in the activated form of F VII was observed. In contrast, no difference was found in F VII clearance. High lipid levels favour the process of thrombus formation by increasing the activation of vitamin K-dependent coagulation factors. Low-dose warfarin treatment reverts the prothrombotic effect of hyperlipidemia.

Topics: Administration, Oral; Animals; Anticoagulants; Aorta, Abdominal; Aortic Diseases; Blood Coagulation Factors; Blood Vessel Prosthesis; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Enzyme Activation; Factor VII; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Postoperative Complications; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Thrombophilia; Thrombosis; Vitamin K; Warfarin

Vitamin K2(K2), a therapeutic agent osteoporosis, is prohibited for patients with thrombosis who are receiving warfarin (WF). However, because some aged patients with thrombosis have osteoporosis, some patients treated with WF may be administered K2 concomitantly. We investigated here the interaction between K2 and WF on thrombosis in a rat aorta loop model. Administration of WF at 0.58, 0.82 and 1.16 mg/l in drinking water for 7 days decreased the thrombotic rate and increased the death rate, dose-dependently. Therefore in the following study, 0.80 mg/l of WF was used. After 2 days of WF-treatment, 1.5, 14 and 145 mg/kg of K2 was administered for 5 days. The blood coagulation time was markedly prolonged by WF treatment for 7 days and this effect was completely inhibited by all doses of K2. WF treatment significantly decreased the cumulative thrombotic rate for 5 days. Administration of 1.5 and 14 mg/kg of K2 did not influence the WF effect on thrombosis. The thrombotic rate in the 145 mg/kg K2 group was lower than that in the WF-control group, but similar to that in the WF-untreated group. These findings suggest that high dose of K2 reduces the effect of WF on thrombosis but does not enhance the occurrence of thrombosis more than that without WF treatment.

Topics: Animals; Aortic Diseases; Drug Interactions; Male; Rats; Rats, Sprague-Dawley; Thrombosis; Vitamin K; Warfarin

Protein-bound gamma-carboxyglutamate (Gla) has been demonstrated in calcified atherosclerotic plaques. Vitamin K is required for the formation of Gla-residues. As the biological activity of Gla-proteins appears to be strictly dependent on the presence of the Gla-residues, vitamin K status may be an important factor in the development and progression of atherosclerotic calcifications. We studied the association of vitamin K status, as assessed by nutritional vitamin K intake and the measurements of two circulating immunoreactive osteocalcin (irOC) fractions, with aortic atherosclerosis in a population-based study of 113 postmenopausal women. Women with calcified lesions (n = 34) had a 42.9 micrograms lower mean age-adjusted dietary vitamin K intake/day (95% C.I. -6.6 to 92.5) than those without calcifications (n = 79). Atherosclerotic women had higher irOC levels with a low affinity for hydroxyapatite (irOCfree): age-adjusted difference of 0.32 ng/ml (95% C.I. 0.03 to 0.61). In addition, the high affinity irOC levels expressed as a percentage (hydroxyapatite binding capacity, HBC) were 5.12% (95% C.I. 1.32 to 8.92) lower in women with calcifications. Our study indicates that women with aortic atherosclerosis have an impaired vitamin K status as reflected by a lower nutritional vitamin K intake, an increased irOCfree level and a reduced HBC level. An impaired vitamin K status in subjects with atherosclerosis is compatible with the view that vitamin K or Gla-containing proteins are involved in the development of calcification of the vessel wall.

Topics: 1-Carboxyglutamic Acid; Aged; Aorta, Abdominal; Aortic Diseases; Arteriosclerosis; Body Constitution; Body Mass Index; Calcinosis; Chromatography, Affinity; Cohort Studies; Diet; Durapatite; Female; Humans; Middle Aged; Osteocalcin; Vitamin K; Vitamin K Deficiency