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1.  Mechanisms of arterial remodeling: lessons from genetic diseases 
Frontiers in Genetics  2012;3:290.
Vascular disease is still the leading cause of morbidity and mortality in the Western world, and the primary cause of myocardial infarction, stroke, and ischemia. The biology of vascular disease is complex and still poorly understood in terms of causes and consequences. Vascular function is determined by structural and functional properties of the arterial vascular wall. Arterial stiffness, that is a pathological alteration of the vascular wall, ultimately results in target-organ damage and increased mortality. Arterial remodeling is accelerated under conditions that adversely affect the balance between arterial function and structure such as hypertension, atherosclerosis, diabetes mellitus, chronic kidney disease, inflammatory disease, lifestyle aspects (smoking), drugs (vitamin K antagonists), and genetic abnormalities [e.g., pseudoxanthoma elasticum (PXE), Marfan's disease]. The aim of this review is to provide an overview of the complex mechanisms and different factors that underlie arterial remodeling, learning from single gene defect diseases like PXE, and PXE-like, Marfan's disease and Keutel syndrome in vascular remodeling.
doi:10.3389/fgene.2012.00290
PMCID: PMC3521155  PMID: 23248645
arterial remodeling; calcification; genetic disease; vitamin K; vitamin K-antagonists
2.  Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women 
Nutrition Journal  2012;11:93.
Background
Vitamin K2 contributes to bone and cardiovascular health. Therefore, two vitamin K2 homologues, menaquinone-4 (MK-4) and menaquinone-7 (MK-7), have been used as nutrients by the food industry and as nutritional supplements to support bone and cardiovascular health. However, little is known about the bioavailability of nutritional MK-4. To investigate MK-4 and MK-7 bioavailability, nutritional doses were administered to healthy Japanese women.
Findings
Single dose administration of MK-4 (420 μg; 945 nmol) or MK-7 (420 μg; 647 nmol) was given in the morning together with standardized breakfast. MK-7 was well absorbed and reached maximal serum level at 6 h after intake and was detected up to 48 h after intake. MK-4 was not detectable in the serum of all subjects at any time point. Consecutive administration of MK-4 (60 μg; 135 nmol) or MK-7 (60 μg; 92 nmol) for 7 days demonstrated that MK-4 supplementation did not increase serum MK-4 levels. However, consecutive administration of MK-7 increased serum MK-7 levels significantly in all subjects.
Conclusions
We conclude that MK-4 present in food does not contribute to the vitamin K status as measured by serum vitamin K levels. MK-7, however significantly increases serum MK-7 levels and therefore may be of particular importance for extrahepatic tissues.
doi:10.1186/1475-2891-11-93
PMCID: PMC3502319  PMID: 23140417
Vitamin K2; Menaquinone-4; Menaquinone-7; Bioavailability; Absorption
3.  Vitamin K Intake and Plasma Desphospho-Uncarboxylated Matrix Gla-Protein Levels in Kidney Transplant Recipients 
PLoS ONE  2012;7(10):e47991.
Vitamin K is essential for activation of γ-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (n = 60) with stable renal function (creatinine clearance 61 [42–77] (median [interquartile range]) ml/min), who were 75 [35–188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, p = 0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.
doi:10.1371/journal.pone.0047991
PMCID: PMC3485347  PMID: 23118917
4.  Vitamin K-Antagonists Accelerate Atherosclerotic Calcification and Induce a Vulnerable Plaque Phenotype 
PLoS ONE  2012;7(8):e43229.
Background
Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.
Methodology/Principal Findings
A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.
Conclusions/Significance
VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.
doi:10.1371/journal.pone.0043229
PMCID: PMC3430691  PMID: 22952653
5.  Administration of vitamin K does not counteract the ectopic mineralization of connective tissues in Abcc6−/− mice, a model for pseudoxanthoma elasticum 
Cell Cycle  2011;10(4):701-707.
Pseudoxanthoma elasticum (PXE) is a heritable multisystem disorder manifesting with ectopic calcification of peripheral connective tissues, caused by mutations in the ABCC6 gene. Alterations in vitamin K metabolism have been suggested to contribute to the pathomechanisms of the mineralization process. In this study we administered vitamin K or its glutathione conjugate (K3-GSH) into Abcc6−/− mice that recapitulate features of PXE. Oral administration of vitamin K2, in dosages that vastly exceed the amounts in control diet or the recommended amounts for humans, did not alter the ectopic mineralization in Abcc6−/− mice. Similarly, intravenous administration of K3-GSH did not alter the degree of mineralization. Testing of vitamin K2, K3 and K3-GSH in an in vitro calcification system provided no evidence of mineralization inhibition. Collectively, our data suggest that vitamin K deficiency in the peripheral tissues is not a simple explanation for development of mineral deposits in PXE.
doi:10.4161/cc.10.4.14862
PMCID: PMC3173996  PMID: 21304270
pseudoxanthoma elasticum; ectopic mineralization; vitamin K; Abcc6 knock-out mouse; Gla proteins
6.  Rapidly Progressive Severe Vascular Calcification Sparing the Kidney Allograft Following Warfarin Initiation 
We describe a case of rapid onset of vascular calcification coincident with the initiation of warfarin therapy in a kidney transplant patient. Calcification developed within the media of the blood vessel wall, with relative intimal sparing. Medium and small sized arteries were affected, but the aorta was mostly free of calcifications, suggesting a differential response to warfarin between the intima and media as well as between different vascular beds. In addition, unlike the highly calcified native kidney’s vessels, the kidney allograft was not calcified, suggesting local, genetically determined, mechanisms in preventing vascular calcification. Distal subcutaneous necrosis ultimately lead to the patient’s demise.
doi:10.1053/j.ajkd.2010.06.017
PMCID: PMC2991526  PMID: 20817370
vascular calcification; warfarin; hemodialysis; MGP
7.  Vitamin K supplementation increases vitamin K tissue levels but fails to counteract ectopic calcification in a mouse model for pseudoxanthoma elasticum 
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder in which calcification of connective tissue leads to pathology in skin, eye and blood vessels. PXE is caused by mutations in ABCC6. High expression of this transporter in the basolateral hepatocyte membrane suggests that it secretes an as-yet elusive factor into the circulation which prevents ectopic calcification. Utilizing our Abcc6−/− mouse model for PXE, we tested the hypothesis that this factor is vitamin K (precursor) (Borst et al. 2008, Cell Cycle). For 3 months, Abcc6−/− and wild-type mice were put on diets containing either the minimum dose of vitamin K required for normal blood coagulation or a dose that was 100 times higher. Vitamin K was supplied as menaquinone-7 (MK-7). Ectopic calcification was monitored in vivo by monthly micro-CT scans of the snout, as the PXE mouse model develops a characteristic connective tissue mineralization at the base of the whiskers. In addition, calcification of kidney arteries was measured by histology. Results show that supplemental MK-7 had no effect on ectopic calcification in Abcc6−/− mice. MK-7 supplementation increased vitamin K levels (in skin, heart and brain) in wild-type and in Abcc6−/− mice. Vitamin K tissue levels did not depend on Abcc6 genotype. In conclusion, dietary MK-7 supplementation increased vitamin K tissue levels in the PXE mouse model but failed to counteract ectopic calcification. Hence, we obtained no support for the hypothesis that Abcc6 transports vitamin K and that PXE can be cured by increasing tissue levels of vitamin K.
doi:10.1007/s00109-011-0782-y
PMCID: PMC3195265  PMID: 21725681
Pseudoxanthoma elasticum; ABC transporter; Vitamin K; Ectopic calcification; Vascular calcification; Connective tissue; Cardiovascular; Vitamins; Calcium metabolism; Mouse models
8.  The Association of Uncarboxylated Matrix Gla Protein with Mitral Annular Calcification Differs by Diabetes Status: The Heart and Soul Study 
Atherosclerosis  2009;210(1):320-325.
Objective
Mitral annular calcification (MAC) and aortic stenosis (AS) are associated with systemic calcification and cardiovascular disease (CVD) events. Matrix Gla protein (MGP) is an inhibitor of vascular calcification and lower levels of its precursor – uncarboxylated MGP (ucMGP) – are associated with vascular calcification in pilot studies.
Methods and Results
In this cross-sectional study of 839 outpatients with stable CVD, we measured serum ucMGP, and evaluated MAC and AS by echocardiography. The association of ucMGP with MAC differed by diabetes status (interaction P<0.001). Among participants without diabetes (n=615), higher ucMGP (per standard deviation [1,178 nM] increase) was associated with lower odds of MAC (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.55-0.97) in models adjusted for traditional CVD risk factors, C-reactive protein, and kidney function. Among persons with diabetes (n=221), higher ucMGP was associated with higher odds of MAC (OR 1.89; 95% CI 1.29-2.78). Results were qualitatively similar for the association of ucMGP with AS although not statistically significant.
Conclusions
Among outpatients with stable CVD, higher ucMGP is associated with lower odds of MAC in persons without diabetes, and higher odds of MAC in persons with diabetes. Future studies should determine whether ucMGP levels are associated with CVD events, and whether such associations differ by diabetes status.
doi:10.1016/j.atherosclerosis.2009.11.023
PMCID: PMC2862076  PMID: 20015492
aortic stenosis; calcification; diabetes mellitus; matrix Gla protein; mitral annular calcification
9.  The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study 
Annals of internal medicine  2010;152(10):640-648.
Background
Fibroblast growth factor 23 (FGF23), uncarboxylated matrix Gla protein (ucMGP), and fetuin-A are regulators of mineral metabolism and inhibitors of vascular calcification. Whether circulating levels of each are associated with cardiovascular disease (CVD) events or mortality in populations without end-stage renal disease is unknown.
Objective
To evaluate the associations of FGF23, ucMGP, and fetuin-A with mortality and CVD events.
Design
Observational study.
Setting
12 outpatient clinics in the San Francisco Bay area.
Patients
833 outpatients with stable coronary artery disease (CAD), recruited from 11 September 2000 to 20 December 2002.
Measurements
Fibroblast growth factor 23, ucMGP, and fetuin-A concentrations were measured at baseline. Participants were followed until 1 December 2008 for mortality and CVD events.
Results
During a median follow-up of 6.0 years, 220 participants died and 182 had CVD events. Compared with participants with FGF-23 levels in the lowest tertile, those in the highest tertile had 2-fold greater risk for mortality (hazard ratio [HR], 2.15 [95% CI, 1.43 to 3.24]) and CVD events (HR, 1.83 [CI, 1.15 to 2.91]) after adjustment for traditional CVD risk factors, C-reactive protein levels, and kidney function. The highest ucMGP tertile was associated with lower mortality risk (HR, 0.48 [CI, 0.31 to 0.75]) and showed a nonsignificant trend toward lower CVD event risk by tertile analysis (HR, 0.65 [CI, 0.40 to 1.05])—an association that was significant when modeled continuously (P = 0.029). No significant association of fetuin-A with mortality (HR, 0.84 [CI, 0.55 to 1.27]) or CVD events (HR, 0.99 [CI, 0.64 to 1.55]) was observed.
Limitation
Participants had prevalent CAD.
Conclusion
In outpatients with stable CAD, higher FGF23 and lower ucMGP levels are independently associated with mortality and CVD events.
Primary Funding Source
American Heart Association.
doi:10.1059/0003-4819-152-10-201005180-00004
PMCID: PMC3079370  PMID: 20479029
10.  Mutations in the GGCX and ABCC6 Genes in a Family with Pseudoxanthoma Elasticum-like Phenotypes 
A characteristic feature of classic PXE, an autosomal recessive disorder caused by mutations in the ABCC6 gene, is aberrant mineralization of connective tissues, particularly the elastic fibers. Here, we report a family with PXE-like cutaneous features in association with multiple coagulation factor deficiency, an autosomal recessive disorder associated with GGCX mutations. The proband and her sister, both with severe skin findings with extensive mineralization, were compound heterozygotes for missense mutations in the GGCX gene, which were shown to result in reduced γ-glutamyl carboxylase activity and in under-carboxylation of matrix gla protein. The proband’s mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (p.V255M) in GGCX and a null mutation (p.R1141X) in the ABCC6 gene, suggesting digenic nature of their skin findings. Thus, reduced γ-glutamyl carboxylase activity in individuals either compound heterozygous for a missense mutation in GGCX or with haploinsufficiency in GGCX in combination with heterozygosity for ABCC6 gene expression results in aberrant mineralization of skin leading to PXE-like phenotype. These findings expand the molecular basis of PXE-like phenotypes, and suggest a role for multiple genetic factors in pathologic tissue mineralization in general.
doi:10.1038/jid.2008.271
PMCID: PMC2900916  PMID: 18800149
11.  Association of kidney function and uncarboxylated matrix Gla protein: Data from the Heart and Soul Study 
Nephrology Dialysis Transplantation  2009;24(7):2095-2101.
Background. Vascular calcification is highly prevalent in persons with chronic kidney disease (CKD) and predicts cardiovascular disease (CVD) events. Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification, and lower levels of its precursor—uncarboxylated MGP (ucMGP)—are associated with vascular calcification and atherosclerosis. Whether mild to moderate decrements in kidney function are associated with lower serum ucMGP is unknown.
Methods. In a cross-sectional study among 842 outpatients with stable CVD, estimated glomerular filtration rate (eGFR), serum cystatin-C and urine albumin-to-creatinine ratio (ACR) were measured and serum ucMGP levels were determined by ELISA. Multivariate linear regression evaluated the association of each kidney function measure with serum ucMGP levels.
Results. The mean eGFR was 76 ± 23 mL/min/1.73 m2, and 186 subjects (22%) had moderate CKD (eGFR <60 mL/min/1.73 m2). The mean ± SD ucMGP level was 3289 ± 1177 nM. In unadjusted analysis, each 10 mL/ min/1.73 m2 lower eGFR was associated with 101 nM lower ucMGP level. This association was only minimally attenuated in final multivariate models wherein each 10 mL/ min/1.73 m2 lower eGFR was associated with 79 nM lower ucMGP (95% confidence interval [CI]; 44 to 115; P < 0.001) after adjustment for age, sex, race, body mass index, blood pressure, smoking, hypertension, diabetes; and serum albumin, calcium, phosphorus, and fetuin-A levels. Similarly, in models adjusted for identical covariates, each 0.1 mg/L higher cystatin-C was associated with 39 nM lower ucMGP (95% CI 23 to 55; P < 0.001). In contrast, no significant association was observed between ACR and ucMGP in either unadjusted or adjusted analyses (adjusted P = 0.17). All associations were similar among subjects with or without diabetes (P-values for interaction > 0.50).
Conclusions. Among outpatients with stable CVD, a reduced glomerular filtration rate is associated with a decreased serum ucMGP level. In contrast, ACR is not associated with ucMGP levels. Whether ucMGP is a useful marker of vascular calcification and CVD event risk in persons with CKD deserves future study.
doi:10.1093/ndt/gfp024
PMCID: PMC2721482  PMID: 19204017
atherosclerosis; chronic kidney disease; matrix Gla protein; vascular calcification
12.  Matrix gla protein (MGP): an overexpressed and migration-promoting mesenchymal component in glioblastoma 
BMC Cancer  2009;9:302.
Background
Recent studies have demonstrated that a molecular subtype of glioblastoma is characterized by overexpression of extracellular matrix (ECM)/mesenchymal components and shorter survival. Specifically, gene expression profiling studies revealed that matrix gla protein (MGP), whose function has traditionally been linked to inhibition of calcification of arteries and cartilage, is overexpressed in glioblastomas and associated with worse outcome.
Methods
In order to analyze the role of MGP in glioblastomas, we performed expression, migration and proliferation studies.
Results
Real-time PCR and ELISA assays confirmed overexpression of MGP in glioblastoma biopsy specimens and cell lines at mRNA and protein levels as compared to normal brain tissue. Immunohistochemistry verified positivity of glial tumor cells for MGP. RNAi-mediated knockdown of MGP in three glioma cell lines (U343MG, U373MG, H4) led to marked reduction of migration, as demonstrated by wound healing and transwell assays, while no effect on proliferation was seen.
Conclusion
Our data suggest that upregulation of MGP (and possibly other ECM-related components as well) results in unfavorable prognosis via increased migration.
doi:10.1186/1471-2407-9-302
PMCID: PMC2739228  PMID: 19712474
13.  Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6−/−) 
Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6−/−, to examine the mineralization processes. We focused on matrix gla protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6−/− mice was significantly reduced when compared to wild-type controls (p<0.004). More importantly, MGP isolated from the liver of Abcc6−/− mice was largely under-carboxylated, and therefore possesses no activity. Finally, examination of the Abcc6−/− mice revealed association of total and under-carboxylated forms of MGP with ectopic mineralization while the γ-carboxylated form was essentially absent. These results suggest that MGP in Abcc6−/− mice is largely in inactive form and is unable to prevent the unwanted mineralization of connective tissues in PXE.
doi:10.1016/j.bbrc.2007.09.122
PMCID: PMC2700335  PMID: 17942075
Pseudoxanthoma elasticum; connective tissue mineralization; matrix gla protein; γ-glutamyl carboxylation; ABC transporters

Results 1-13 (13)