osteoprotegerin and Aortic-Diseases

Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor κB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease.

Topics: Aging; Aortic Diseases; Atherosclerosis; Blood Flow Velocity; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Gene Expression; Humans; Inflammation; Lipids; Obesity; Osteoprotegerin; Polymorphism, Genetic; Prognosis; Vascular Calcification

Topics: Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Calcinosis; Cells, Cultured; Cholesterol, Dietary; Chondrogenesis; Diet, High-Fat; Dietary Fats; Gene Expression Regulation; Interleukin-6; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Osteoprotegerin; Random Allocation; RANK Ligand; Toll-Like Receptor 2

We hypothesized that circulating osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels could be associated with vascular calcification, which is predominant in diabetes.The study included 71 Korean participants (36 with diabetes and 35 without diabetes), who were sub-grouped according to the results of the ankle-brachial index (ABI) and/or X-ray computed tomography scan (CT scan). Serum OPG and TRAIL levels were assayed using the respective enzyme-linked immunosorbent assay kits. Statistical significance was analyzed using Student's t test between the 2 groups or analysis of variance (ANOVA) among the 4 groups.Serum OPG was up-regulated in the participants with diabetes, with peripheral arterial disease (PAD), and/or with vascular calcification. TRAIL down-regulation was more strictly controlled than OPG up-regulation; it was significantly downregulated in the participants with PAD and vascular calcification, but not in the participants with diabetes. Serum OPG and TRAIL were regulated in the participants with femoral, popliteal, and peroneal artery calcification but not in the participants with aortic calcification.OPG up-regulation and TRAIL down-regulation were found to be associated with leg lesional vascular calcification; therefore, the average OPG/TRAIL ratio was significantly increased by 3.2-fold in the leg lesional vascular calcification group.

Topics: Aortic Diseases; Biomarkers; Diabetes Complications; Humans; Leg; Osteoprotegerin; Peripheral Arterial Disease; TNF-Related Apoptosis-Inducing Ligand; Vascular Calcification

Vascular calcifications (VCs) are a cardiovascular risk factor in patients affected by chronic kidney disease and after kidney transplantation (KTx). We evaluated the prevalence of VCs at the abdominal aortic site in KTx patients at the time of transplantation and 1 year after KTx, exploring the possibly associated factors.. In 107 transplanted patients, the following parameters were evaluated at the first and twelfth month after KTx: the aortic calcification index (ACI), fibroblast growth factor 23, osteoprotegerin (OPG), fetuin A, and clinical and biochemical parameters. Patients were followed up for 2 years after KTx.. At the time of KTx, 60% of patients had some degree of VC (ACI>0), whereas 40% had no VC. One year after KTx, VCs worsened in 26% of patients, whereas in 74%, VCs remained stable or improved. The progression of VC was observed almost exclusively in patients with a positive ACI score at the first month. At the multivariate analysis, serum calcium, OPG, and estimated glomerular filtration rate were the only variables independently associated with the progression of VC.. VCs at the aortic site are frequent in KTx patients, and in a significant percentage of them, they tend to progress even in the short time. High levels of serum calcium and OPG are significantly associated with the progression of VCs. Whether these associations are based on a cause-effect relationship and their correction might impact on the calcification process could be ascertained by prospective interventional studies.

Topics: Adult; Aorta, Abdominal; Aortic Diseases; Biomarkers; Calcium; Cohort Studies; Disease Progression; Female; Humans; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Postoperative Complications; Predictive Value of Tests; Prevalence; Risk Factors; Vascular Calcification

To assess the association of circulating bone marrow-derived osteo-progenitors with vascular calcification in mouse models and patients with peripheral artery disease.. We estimated the percentage of circulating mononuclear cells expressing osteocalcin in 2 mouse models of aortic calcification developed in osteoprotegerin-deficient mice (OPG(-/-)) using flow cytometry. Aortic calcification was assessed in mice principally by a bioassay of harvested aortas. In patients with peripheral artery disease osteocalcin-positive cells (estimated by flow cytometry) were related to aortic calcification volume assessed from computed tomography.. The amount of extractable aortic calcium was increased in both mouse models used in comparison to controls. The percentage of circulating mononuclear cells expressing osteocalcin was correlated to the amount of extractable aortic calcium in male (r=0.525, p=0.02) and female OPG(-/-) (r=0.564, p=0.02) mice and also in animals in which calcification was accelerated using calcitriol (r=0.64, p=0.01). Patients with more severe aortic calcification had a greater percentage of circulating OCN(+) MNCs (median 4.07%, IQR 3.76-4.39, n=12) than those with less severe aortic calcification (median 3.10%, IQR 2.32-3.60, n=11, p=0.05).. This study demonstrates that aortic calcification can be robustly quantified in 2 mouse models. In these models and patients with peripheral artery disease circulating osteocalcin positive mononuclear cells are associated with the severity of aortic calcification.

Topics: Animals; Aorta; Aortic Diseases; Calcinosis; Calcium; Disease Models, Animal; Female; Flow Cytometry; Humans; Leukocytes, Mononuclear; Male; Mice; Osteocalcin; Osteoprotegerin; Peripheral Vascular Diseases; Severity of Illness Index; Stem Cells; Tomography, X-Ray Computed

We investigated whether gene polymorphisms of Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and matrix metalloproteinase 3 (MMP3) are associated with increased vascular calcification in patients with type 2 diabetes (T2D) and evaluated whether serum MMP3 and osteoprotegerin (OPG) levels are related to calcification.. This study included 464 subjects: 269 patients with T2D and 195 healthy controls in South Korea. We genotyped subjects for four single nucleotide polymorphisms (SNPs): ENPP1 K121Q, ENPP1 A/G+1044TGA, MMP3 -709A>G and MMP3 -1475G>A. The presence or absence of calcifications in the aortic arch was assessed by plain chest radiography.. The SNPs ENPP1 K121Q and MMP3 -709A>G showed significant associations with T2D (P=0.001 and P=0.004). The SNP ENPP1 K121Q showed a significant association with aortic arch calcification in T2D (P=0.036). Serum OPG levels were significantly higher in T2D patients than in the control group (P<0.001). However, serum MMP3 levels were significantly lower in T2D patients than in the control group (P<0.001).. Our study demonstrates that the ENPP1 K121Q and MMP3 -709A>G polymorphisms are associated with T2D, and that the ENPP1 Q allele is associated with increased aortic arch calcification in a Korean population.

Topics: Adult; Aged; Alleles; Analysis of Variance; Aortic Diseases; Asian People; Body Composition; Calcinosis; Chi-Square Distribution; Diabetes Mellitus, Type 2; Diet; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Matrix Metalloproteinase 3; Middle Aged; Osteoprotegerin; Phosphoric Diester Hydrolases; Polymorphism, Single Nucleotide; Pyrophosphatases; Regression Analysis; Republic of Korea

Coral reef aorta is a rare vascular disease with intraluminal calcifications of the dorsal part of the visceral aorta. The pathogenesis of this disease with its topographic and morphologic characteristics is unknown. The aim of our study was to investigate calcification inhibitors and the ultrastructure of calcifications in patients with coral reef aorta.. Ten patients with coral reef aorta were examined. Calcified specimens were investigated by immunohistochemical techniques for the expression of the calcification inhibitors matrix gla protein (MGP) and fetuin-A. Vessel walls were also assessed by electron microscopic techniques including electron energy-lost spectroscopy, electron dispersive spectroscopy, and electron diffraction. Sera of patients were analyzed for fetuin-A, uncarboxylated MGP (ucMGP), and osteoprotegerin.. As assessed by immunohistochemistry, most MGP was detected in the vicinity of calcified regions. Serum levels of the calcification inhibitors ucMGP, fetuin-A, and osteoprotegerin were 370+/-107 nmol/L, 0.57+/-0.03 g/L, and 5.64+/-0.79 pmol/L, respectively. Ultrastructural analysis of calcified specimens showed a core-shell structure with multiple calcification nuclei. Calcifications displayed a fine-crystalline character, and elemental analysis revealed hydroxyl apatite as the chemical compound.. The coral reef aorta represents an extreme exophytic growth of vascular calcification with multiple nuclei which resemble typical media calcification. Positive vascular immunostaining and low serum levels of both fetuin-A and ucMGP suggest a pathophysiologic role of these calcification inhibitors in the development of coral reef aorta.

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Aorta; Aortic Diseases; Aortography; Biomarkers; Blood Proteins; Calcinosis; Calcium-Binding Proteins; Durapatite; Extracellular Matrix Proteins; Female; Humans; Immunohistochemistry; Male; Matrix Gla Protein; Microscopy, Electron, Scanning; Middle Aged; Osteoprotegerin; Prospective Studies; Retrospective Studies; Tomography, X-Ray Computed

Vascular calcifications (VCs) are important predictors of cardiovascular mortality in patients with chronic kidney disease (CKD). We have shown previously that osteoprotegerin (OPG), a potential early biomarker for VC, was an independent predictor of mortality in CKD patients. The aim of our study was to follow longitudinally coronary and aortic VCs. VCs were measured using Siemens 16 detector CT in a group of predialysis and hemodialyzed patients before and after a follow-up of 4 years. Some of these patients were transplanted in the meantime. Renal function, calcium, phosphate, iPTH, hs-CRP (high sensitive protein C reactive), and OPG serum levels were also compared. VCs progressed in predialysis, hemodialyzed, and transplanted patients but the progression was not the same in all arterial beds. A progression of coronary calcifications was observed in predialysis and transplanted patients, while aortic calcifications worsened significantly only in hemodialyzed patients. OPG serum levels and hs-CRP were significantly lower among transplanted patients. We concluded that VC depends on the severity of the kidney disease. Transplanted patients are not protected from VC, yet their OPG serum levels were significantly lower, suggesting that there is no link between between OPG levels and severity of VC. Longer follow-up of these patients would be necessary to assess whether a decline in OPG correlates with better survival.

Topics: Adult; Aged; Aortic Diseases; Belgium; Biomarkers; Calcinosis; Coronary Artery Disease; Female; Humans; Kidney Diseases; Kidney Transplantation; Least-Squares Analysis; Linear Models; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prognosis; Renal Dialysis; Severity of Illness Index; Time Factors; Tomography, X-Ray Computed

Osteoprotegerin (OPG) inhibits interaction of the receptor-activator of nuclear factor-kappaB (RANK) ligand (RANKL) with its receptor RANK, which is expressed on osteoclasts. OPG appeared to accelerate vascular calcification in vitro by the inhibition of vascular osteoclast-like cells. On the contrary, early-onset arterial calcification was observed in OPG-deficient mice. We measured the coronary artery calcification score (CACS) and abdominal aortic calcification score (AAoCS) by multi-detector computed tomography in 30 pre-dialysis CKD patients (eGFR 20 mL/min on average). Biomarkers were measured, including serum OPG, soluble RANKL (sRANKL) and tartrate-resistant acid phosphatase (TRACP) -5b (the biomarker of osteoclasts independent of renal function). The median values of CACS and AAoCS were 54.4 and 1,088 Agatston units (AU), respectively. Serum OPG was increased and serum sRANKL was decreased. In a multivariate logistic regression analysis using CACS > or = 100 AU as the outcome variable, CACS was found to be positively correlated with serum corrected Ca x iP product and serum OPG, though it was not correlated with serum TRACP-5b. ROC curve analysis showed that the serum OPG cutoff value predicting CACS > or = 100 AU was 5.2 pmol/L (624 pg/mL). In a stepwise regression analysis, log (AAoCS + 1) was positively correlated with serum OPG alone, but it was not correlated with age, eGFR, serum albumin and bone alkaline phosphatase (BAP). No correlation was found between serum OPG and serum TRACP-5b. In conclusion, vascular calcification in pre-dialysis CKD patients was correlated with an increase in OPG, but was independent of serum TRACP-5b. The decrease in serum sRANKL may have been caused by the increase in OPG production.

Topics: Acid Phosphatase; Aorta, Abdominal; Aortic Diseases; Biomarkers; Calcinosis; Coronary Disease; Coronary Vessels; Dialysis; Female; Humans; Isoenzymes; Logistic Models; Male; Osteoclasts; Osteoprotegerin; RANK Ligand; Tartrate-Resistant Acid Phosphatase

Vascular calcification commonly associated with several pathologies and it has been suggested to be similar to bone mineralization. The axis RANKL-OPG (receptor activator of nuclear factor kappaB ligand-osteoprotegerin) finely controls bone turnover. RANKL has been suggested to increase vascular calcification, but direct evidence is missing. Thus, in the present work, we assess the effect of RANKL in vascular smooth muscle cell (VSMC) calcification. VSMCs incubated with RANKL showed a dose-dependent increase in calcification, which was abolished by coincubation with OPG. To test whether the effect was mediated by signaling to its receptor, knockdown of RANK was accomplished by short hairpin (sh)RNA. Indeed, cells lacking RANK showed no increases in vascular calcification when incubated with RANKL. To further elucidate the mechanism by which RANK activation increases calcification, we blocked both nuclear factor (NF)-kappaB activation pathways. Only IKKalpha inactivation inhibited calcification, pointing to an involvement of the alternative NF-kappaB activation pathway. Furthermore, RANKL addition increased bone morphogenetic protein (BMP)4 expression in VSMCs, and that increase disappeared in cells lacking RANK or IKKalpha. The increase in calcification was also blunted by Noggin, pointing to a mediation of BMP4 in the calcification induced by RANKL. Furthermore, in an in vivo model, the increase in vascular calcium content was parallel to an increase in RANKL and BMP4 expression, which was localized in calcified areas. However, blood levels of the ratio RANKL/OPG did not change. We conclude that RANKL increases vascular smooth muscle cell calcification by binding to RANK and increasing BMP4 production through activation of the alternative NF-kappaB pathway.

Topics: Animals; Aortic Diseases; Bone Morphogenetic Protein 4; Calcinosis; Calcitriol; Carrier Proteins; Cells, Cultured; Disease Models, Animal; I-kappa B Kinase; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Osteoprotegerin; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B; RNA Interference; RNA, Small Interfering; Signal Transduction

Visceral obesity and aortic calcification are both associated with cardiovascular events. The purpose of this study was to examine if visceral obesity was associated with the severity of abdominal aortic calcification.. One hundred and forty eight patients with peripheral artery disease were assessed by CT angiography. The severity of infrarenal abdominal aortic calcification was measured using a validated technique. The size of the visceral and subcutaneous compartments was estimated from anthropometric measurements made from the same CT. Calcification and anthropometric measurements were compared with Spearman's correlation and multiple logistic regression (adjusting for age, gender, hypertension, diabetes, smoking and cholesterol).. The relative size of the visceral compartment estimated from CT diameter ratios was correlated with abdominal aortic calcification severity, r=0.27, p=0.001 and independently associated with calcification allowing for other cardiovascular risk factors (OR 6.63, 95% CI 1.90-23.14). The relative size of the visceral compartment was associated with serum osteoprotegerin levels, suggesting a possible mechanism underlying the detrimental influence of visceral adiposity.. The association of visceral adiposity and arterial calcification suggests one mechanism, which may contribute to the detrimental effects of central obesity.

Topics: Adipokines; Aged; Angiography; Anthropometry; Aorta, Abdominal; Aortic Diseases; Calcinosis; Cohort Studies; Female; Humans; Intra-Abdominal Fat; Logistic Models; Male; Middle Aged; Obesity; Osteoprotegerin; Risk Factors; Severity of Illness Index; Tomography, X-Ray Computed

Arterial medial calcifications occur often in diabetic individuals as part of the diabetic macroangiopathy. The pathogenesis is unknown, but the presence of calcifications predicts risk of cardiovascular events. We examined the effects of insulin on calcifying smooth muscle cells in vitro and measured the expression of the bone-related molecule osteoprotegerin (OPG). Human vascular smooth muscle cells (VSMCs) were grown from aorta from kidney donors. Induction of calcification was performed with beta-glycerophosphate. The influence of insulin (200 microU/ml or 1,000 microU/ml) on calcification was judged by measuring calcium content in the cell layer and by von Kossa staining. OPG was measured in the medium by ELISA. Histochemistry was used for determination of alkaline phosphatase (ALP). Bone sialoprotein (BSP) and OPG mRNA expressions were done by RT-PCR. beta-Glycerophosphate was able to induce calcification in human smooth muscle cells from a series of donors after variable time in culture. Decreased OPG amounts were observed from the cells during the accelerated calcification phase. High dose of insulin (1,000 microU/ml) accelerated the calcification, whereas lower concentrations (200 microU/ml) did not. Calcified cells expressed ALP and BSP activity in high levels. In conclusion, high concentration of insulin enhances in vitro-induced calcification in VSMCs. Altered OPG levels during the calcification raise the possibility that OPG may have a potent function in regulating the calcification process or it may represent a consequence of mineralization. Effects of insulin and modulations by OPG on the calcification process in arterial cells may play a role in the development of calcifications as part of the diabetic macroangiopathy.

Topics: Alkaline Phosphatase; Aorta; Aortic Diseases; Calcinosis; Calcium; Cells, Cultured; Diabetic Angiopathies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glycerophosphates; Humans; Insulin; Integrin-Binding Sialoprotein; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoprotegerin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sialoglycoproteins; Time Factors

Topics: Aorta, Abdominal; Aortic Diseases; Calcinosis; Glycoproteins; Humans; Osteopontin; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Severity of Illness Index; Sialoglycoproteins

Topics: Aorta, Abdominal; Aortic Diseases; Bone Density; Calcinosis; Cohort Studies; Female; Fractures, Bone; France; Glycoproteins; Humans; Middle Aged; Osteoporosis; Osteoprotegerin; Prevalence; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors

Takayasu arteritis (TA) is a chronic inflammatory disorder affecting the aorta and its branches. Vascular calcification has been described in 29-54% of cases of TA, although its aetiology remains unknown. Recently the osteoprotegerin/RANKL/RANK system has emerged as an important contributing factor to atherogenesis and osteogenesis. Our aim is to investigate the association between vascular calcification, bone mineral density (BMD) and the osteoprotegerin/RANK/RANKL system in TA.. Thirty pre-menopausal female TA patients and 30 age- and sex-matched controls were studied. BMD was measured by dual X-ray absorptiometry. Arterial calcification in TA patients was analysed by computed tomography in thoracic and abdominal sites. Serum levels of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) were quantified by enzyme-linked immunosorbent assay.. Patients with severe arterial calcification showed lower BMD values than controls in lumbar spine (0.965 +/- 0.055 vs 1.126 +/- 0.153 g/cm2, P = 0.009) and total body (0.993 +/- 0.065 vs 1.085 +/- 0.082 g/cm2, P = 0.019). In contrast, TA patients without calcification presented BMD values similar to controls (P > 0.05). Interestingly, lower serum levels of sRANKL (1.89 +/- 2.35 vs 2.80 +/- 2.23 pg/ml, P = 0.031) and a longer disease duration (12.20 +/- 6.61 vs 3.56 +/- 5.33 yr, P = 0.004) were observed in TA patients with severe calcification compared with patients without calcification.. Severe arterial calcification in TA is associated with low values of BMD and sRANKL, reinforcing the possible link between bone and vascular disease.

Topics: Adult; Aortic Diseases; Bone Density; Bone Diseases, Metabolic; Calcinosis; Carrier Proteins; Female; Glycoproteins; Humans; Lumbar Vertebrae; Membrane Glycoproteins; Osteoprotegerin; Premenopause; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Takayasu Arteritis

The present studies were carried out to evaluate the possible association between the presence of the fetuin-mineral complex in serum and vitamin D-induced artery calcification. The first experiment shows that there is a fetuin-mineral complex in the blood of rats in which extensive calcification of the artery media has been induced by treatment with vitamin D for 96 h, and that there is no detectable fetuin-mineral complex in the blood of rats in which artery calcification has been inhibited by concurrent treatment with ibandronate or osteoprotegerin. The second experiment shows that the timing of vitamin D-induced artery calcification correlates with the timing of the maximal increase in serum fetuin-mineral complex levels. Whereas both results indicate that serum levels of the fetuin-mineral complex are indeed associated with vitamin D-induced artery calcification, the biochemical basis for this association is presently unclear. One possibility is that high levels of the fetuin-mineral complex cause defects in the ability of fetuin to prevent the growth of the mineral component, which then seeds artery calcification. Another possibility is that the fetuin-mineral complex is the downstream product of a pathway that begins with the true causative agent, and that the serum level of the fetuin-mineral complex is a marker for the activity of this agent in blood. An unexpected finding of the present studies is that vitamin D-induced artery calcification is also correlated with a 65 to 75% reduction in serum fetuin, a reduction that appears to be caused by the clearance of the fetuin-mineral complex from serum.

Topics: alpha-Fetoproteins; Animals; Aorta, Abdominal; Aortic Diseases; Bone Resorption; Calcinosis; Diphosphonates; Glycoproteins; Ibandronic Acid; Male; Minerals; Osteoprotegerin; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vitamin D

Osteoprotegerin (OPG) is a glycoprotein that inhibits osteoclast differentiation and activity. OPG-deficient mice develop severe osteoporosis and medial arterial calcification. The expression of OPG is detected in early atherosclerotic lesions in non-uraemic patients. We examined whether serum OPG is associated with aortic calcification in haemodialysis patients.. Serum OPG was measured in 102 patients who were undergoing haemodialysis. The aortic calcification index (ACI) was assessed by computed tomography scans.. Serum OPG level, measured by enzyme-linked immunosorbent assay, was significantly greater in patients with higher ACI than in those with lower ACI. There was a direct relationship between ACI and serum OPG levels and a positive association between OPG and ACI (r = 0.483, P<0.0001). Multiple regression analyses indicated that serum OPG levels were independently associated with the severity of aortic calcification (P<0.0001).. These findings show that serum OPG levels are associated with the extent of vascular calcification, suggesting that OPG may be involved in the development of vascular calcification in haemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Aortic Diseases; Calcinosis; Female; Glycoproteins; Humans; Male; Middle Aged; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Severity of Illness Index

We have previously shown that an endothelin receptor antagonist can regress medial arterial calcification in a rat model. The aim of this study was to characterize the phenotypic changes of vascular smooth muscle cells during calcification and mineral loss, in order to understand better the underlying mechanisms. Control Wistar rats were compared with rats treated only with warfarin/ vitamin K1 (15 mg/kg per day) for 8 weeks, or in combination with darusentan (30 mg/kg per day) for the final 4 weeks. Vascular smooth muscle cell, bone cell and macrophage phenotypes were evaluated by the local expression of alpha-actin, tartrate-resistant acid phosphatase and ED-1, respectively. Proteins involved in the modulation of bone resorption like osteopontin and osteoprotegerin were also evaluated by immunohistochemistry. The warfarin/vitamin K1 treatment increased medial arterial calcification ninefold (P < 0.05). At sites of calcification, there was a decrease in alpha-actin localization, and an appearance of osteopontin immunostaining. Histochemical and immunostaining for osteoclast and macrophage markers, as well as for osteoprotegerin, were negative. Although the extent of calcification foci was reduced by darusentan, protein localization in the calcified areas was not modified. Thus, the development of medial arterial calcification produces a phenotypic change in vascular smooth muscle cells that does not appear to be normalized in regions remaining calcified during mineral loss.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Macrophages; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoclasts; Osteopontin; Osteoprotegerin; Phenotype; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptors, Endothelin; Vitamin K 1; Warfarin

The aortic calcification index (ACI), estimated on abdominal computed tomographic scans, has been associated with the extent of arteriosclerosis in hemodialysis patients. However, the contribution of biochemical markers to the progression of vascular calcification in patients undergoing hemodialysis is not fully understood.. We examined the relationship between coronary risk factors; metabolic factors, including serum osteoprotegerin (OPG) concentration; and progression of vascular calcification in 26 dialysis patients.. Mean patient age was 52.6 +/- 8.7 (SD) years, and mean duration of dialysis therapy was 7.7 +/- 5.8 years. ACI was measured twice in each patient, and the mean interscan period was 4.9 +/- 0.3 years. Mean ACI changed from 22.2 +/- 24.2 to 33.9 +/- 28.8 overall, and mean change in ACI (DeltaACI) was 12.0 +/- 9.9. Patients were divided into 2 groups: slow progressors, with DeltaACI of 4.1 +/- 3.2 (n = 13), and rapid progressors, with DeltaACI of 19.8 +/- 7.9 (n = 13). Serum fasting glucose and CRP levels of rapid progressors were high, and their serum albumin and intact parathyroid hormone levels were low. Multiple regression analyses showed that serum OPG levels were independently associated with vascular calcification in the hemodialysis patients studied.. Rapid progression of vascular calcification was associated with dose of calcium carbonate prescribed and serum OPG concentration. The clinical significance of these observations remains to be determined.

Topics: Aortic Diseases; Arteriosclerosis; C-Reactive Protein; Calcinosis; Calcium; Calcium Carbonate; Disease Progression; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Lipids; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Phosphorus; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Risk Factors