MGP
Matrix Gla protein precursor (MGP) (Cell growth-inhibiting gene 36 protein) [MGLAP] [GIG36]
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A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk. We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status. Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms. Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension ([i]n[/i] = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension ([i]n[/i] = 153; 48 events) and without hypertension ([i]n[/i] = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status ([i]P[/i]-interaction = 0.72). Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.
MeSH Terms
- Aged
- Aging
- Antihypertensive Agents
- Avitaminosis
- Body Composition
- Calcinosis
- Calcium-Binding Proteins
- Cardiovascular Diseases
- Extracellular Matrix Proteins
- Female
- Humans
- Hypertension
- Male
- Myocardial Infarction
- Myocardial Ischemia
- Proportional Hazards Models
- Risk Factors
- Stroke
- Vitamin K 1
Keywords
- cardiovascular disease
- hypertension
- matrix Gla protein
- phylloquinone
- vitamin K
To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. [i]In silico[/i] DNA methylation analysis of 353 epigenetic clock CpG sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer (CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated age-related genes, secreted frizzled related protein 1 ([i]SFRP1[/i]) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting (MS-HRM) analysis. mRNA expression of age-related "epigenetic clock" genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples (49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children) (GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylation-gene expression data was performed on 30 colonic samples using methyl capture sequencing. Fifty-seven age-related CpG sites including hypermethylated [i]PPP1R16B[/i], [i]SFRP1[/i], [i]SYNE1[/i] and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues ([i]P[/i] < 0.05, Δβ ≥ 10%). In the adenoma [i]vs[/i] normal comparison, 70 CpG sites differed significantly, including hypermethylated [i]DKK3[/i], [i]SDC2[/i], [i]SFRP1[/i], [i]SYNE1[/i] and hypomethylated [i]CEMIP[/i], [i]SPATA18[/i] ([i]P[/i] < 0.05, Δβ ≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC (55.0% ± 8.4 %) and adenoma tissue samples (49.9% ± 18.1%) compared to normal adult (5.2% ± 2.7%) and young (2.2% ± 0.7%) colonic tissue ([i]P[/i] < 0.0001). DNA methylation of [i]SFRP1[/i] promoter was slightly, but significantly increased in healthy adults compared to normal young samples ([i]P[/i] < 0.02). This correlated with significantly increased [i]SFRP1[/i] mRNA levels in children compared to normal adult samples ([i]P[/i] < 0.05). In CRC tissue the mRNA expression of 117 age-related genes were changed, while in adenoma samples 102 genes showed differential expression compared with normal colonic tissue ([i]P[/i] < 0.05, logFC > 0.5). The change of expression for several genes including [i]SYNE1[/i], [i]CLEC3B[/i], [i]LTBP3[/i] and [i]SFRP1[/i], followed the same pattern in aging and carcinogenesis, though not for all genes ([i]e.g[/i]., MGP). Several age-related DNA methylation alterations can be observed during CRC development and progression affecting the mRNA expression of certain CRC- and adenoma-related key control genes.
MeSH Terms
- Adenoma
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers, Tumor
- Biopsy
- Carcinoma
- Case-Control Studies
- Child
- Child, Preschool
- Colorectal Neoplasms
- CpG Islands
- DNA Methylation
- Epigenesis, Genetic
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Infant
- Intercellular Signaling Peptides and Proteins
- Male
- Membrane Proteins
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Polymerase Chain Reaction
- Promoter Regions, Genetic
Keywords
- Adenoma
- Aging
- Colorectal cancer
- DNA methylation
- Epigenetic clock
- Epigenetic drift
- Secreted frizzled related protein 1
Hypertension, osteoporosis and vascular calcification are major diseases in the recent aging society and may share the same backgrounds genetically and environmentally. As treatments to prevent aging-related diseases simultaneously are desirable, we investigate common backgrounds underling these diseases. Renin- angiotensin system, which causes high blood pressure, is found to be involved in bone metabolism. Angiotensin II has been shown to accelerate osteoporosis through RANKL up-regulation in osteoblast. RANKL, in turn, contributes to vascular calcification by regulating bone morphogenetic protein-2 and MGP expression, as well as bone-related proteins. Angiotensin type 1 receptor blockers (ARBs) ameliorate osteoporosis and vascular calcification beyond their blood pressure lowering effects. These pleiotropic effects of antihypertensive drugs such as ARBs might benefit especially hypertensive postmenopausal women.
MeSH Terms
- Aging
- Bone and Bones
- Cardiovascular Diseases
- Humans
- Hypertension
- Osteoporosis
- Renin-Angiotensin System
- Vascular Calcification
Vitamin K plays a pivotal role in the synthesis of Matrix Gla protein (MGP), a calcification inhibitor in vascular tissue. Vascular calcification has become an important predictor of cardiovascular disease. The aim of the current study was to examine the potential association of circulating desphospho-carboxylated and -uncarboxylated MGP (dp-cMGP and dp-ucMGP), reflecting vitamin K status, with the incidence of cardiovascular events and disease (CVD) in older individuals. The study was conducted in 577 community-dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA), aged >55 year, who were free of cardiovascular disease at baseline. Multivariate Cox proportional hazards models were used to analyze the data. Incidence of CVD. After a mean follow-up of 5.6±1.2 year, we identified 40 incident cases of CVD. After adjustment for classical confounders and vitamin D status, we observed a more than 2-fold significantly higher risk of CVD for the highest tertile of dp-ucMGP with a HR of 2.69 (95% CI, 1.09-6.62) as compared with the lowest tertile. Plasma dp-cMGP was not associated with the risk of CVD. Vitamin K insufficiency, as assessed by high plasma dp-ucMGP concentrations is associated with an increased risk for cardiovascular disease independent of classical risk factors and vitamin D status. Larger epidemiological studies on dp-ucMGP and CVD incidence are needed followed by clinical trials to test whether vitamin K-rich diets will lead to a decreased risk for cardiovascular events.
MeSH Terms
- Biomarkers
- Calcium-Binding Proteins
- Cardiovascular Diseases
- Extracellular Matrix Proteins
- Female
- Humans
- Incidence
- Longitudinal Studies
- Male
- Middle Aged
- Netherlands
- Risk Factors
- Vitamin K Deficiency
Keywords
- CVD
- Cardiovascular disease
- Gla
- LASA
- Longitudinal Aging Study Amsterdam
- MGP
- Matrix Gla-protein
- Vitamin K status
- cardiovascular events and disease
- desphospho-carboxylated MGP
- desphospho-uncarboxylated MGP
- dp-cMGP
- dp-ucMGP
- matrix Gla protein
- γ-carboxyglutamate
Matrix gla protein (MGP) is a potent inhibitor of extracellular matrix (ECM) mineralization. MGP-deficiency in humans leads to Keutel syndrome, a rare genetic disease hallmarked by abnormal soft tissue calcification. MGP-deficient (Mgp(-/-)) mice show progressive deposition of hydroxyapatite minerals in the arterial walls and die within 2 months of age. The mechanism of antimineralization function of MGP is not fully understood. We examined the progression of vascular calcification and expression of several chondrogenic/osteogenic markers in the thoracic aortas of Mgp(-/-) mice at various ages. Although cells with chondrocyte-like morphology have been reported in the calcified aorta, our gene expression data indicate that chondrogenic/osteogenic markers are not upregulated in the arteries prior to the initiation of calcification. Interestingly, arterial calcification in Mgp(-/-) mice appears first in the elastic laminae. Considering the known mineral scaffolding function of elastin (ELN), a major elastic lamina protein, we hypothesize that elastin content in the laminae is a critical determinant for arterial calcification in Mgp(-/-) mice. To investigate this, we performed micro-computed tomography (µCT) and histological analyses of the aortas of Mgp(-/-);Eln( /-) mice and show that elastin haploinsufficiency significantly reduces arterial calcification in this strain. Our data suggest that MGP deficiency leads to alterations of vascular ECM that may in turn initiate arterial calcification.
MeSH Terms
- Aging
- Animals
- Antigens, Differentiation
- Aorta, Thoracic
- Durapatite
- Elastin
- Mice
- Mice, Knockout
- Proteins
- Vascular Calcification
- X-Ray Microtomography
Keywords
- ELASTIN
- KEUTEL SYNDROME
- MATRIX GLA PROTEIN
- VASCULAR CALCIFICATION
- VASCULAR SMOOTH MUSCLE CELLS