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PubMed2002

[Osteoporosis and vascular calcification].

Many clinical studies have shown that osteoporosis is associated with atherosclerosis and cardiovascular death. Plasma lipids might be related to bone mass and bone fragility, and might be the common factor underlying both osteoporosis and atherosclerosis. It is interesting that statins, estrogens, and nitrogen-containing bisphosphonates have similar stimulatory effects on bone mass, because all of them are known to reduce LDL-cholesterol (C) and increase HDL-C in the plasma. Thus, these two disorders might be related to each other in terms of pathogenesis and therapeutic agents.

English Abstract↗
PubMed2002

[Diabetes mellitus and vascular calcification].

Two types of arterial calcification are well recognized:intimal (atherosclerotic) and medial (Monckeberg type). These two calcifications are considered different in pathogenesis. Arterial calcification has recently been reported to be an organized, regulated process similar to bone formation. The relation of calcification to diabetes mellitus remains still unclear. EBCT can noninvasively and accurately detect coronary artery calcification. Diabetic patients seem to have increased prevalence of coronary calcification when compared with non-diabetic patients. Medial artery calcification is an independent predictor of cardiovascular mortality in diabetic patients.

English Abstract↗
PubMed2005

[Effects of intermittent treatment with sevelamer hydrochloride on parathyroid hyperplasia and vascular calcification in rats with chronic kidney disease].

Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic kidney disease (CKD). Rats were fed a diet containing adenine for 4 weeks to establish CKD. Animals were then offered a diet containing sevelamer hydrochloride (sevelamer) or a normal diet for alternating 2 week periods over 8 weeks. Adenine-treated rats showed marked elevations of serum phosphorus, PTH and FGF23 levels associated with parathyroid hyperplasia and aortic calcification. Serum phosphorus, PTH and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, intermittent treatment with sevelamer successfully inhibited parathyroid hyperplasia and aortic calcification. In conclusion, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CKD. Setting up a period of reduced serum phosphorus levels, even if it is intermittent, is worthwhile for the inhibition of the development of parathyroid hyperplasia and aortic calcification.

Adenine↗
PubMed1989

[Intracerebral, non-arteriosclerotic vascular calcification: Fahr's disease].

Of 15,000 post-mortem examinations performed in a general hospital between 1977-85 primary symmetric intracerebral calcification i. e. Fahr's disease was found in 4 cases. The pathological characteristics of the cases are described and the clinical, radiological and endocrinological aspects of the disease are discussed.

Aged↗
PubMed2006

Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification.

Vascular calcification is associated with cardiovascular morbidity and mortality. Hyperphosphatemia is an important contributor to vascular calcification. Our previous studies demonstrated that elevated phosphate induces calcification of smooth muscle cells (SMC) in vitro. Inhibition of phosphate transport by phosphonoformic acid blocked phosphate-induced calcification, implicating sodium-dependent phosphate cotransporters in this process. In the present study, we have investigated the role of the type III sodium-dependent phosphate cotransporter, Pit-1, in SMC calcification in vitro. Human SMC stably expressing Pit-1 small interfering double-stranded RNA (SMC-iRNA) were established using a retroviral system. SMC-iRNA had decreased Pit-1 mRNA and protein levels and sodium-dependent phosphate transport activity compared with the control transduced cells (SMC-CT) (2.9 versus 9.78 nmol/mg protein per 30 minutes, respectively). Furthermore, phosphate-induced SMC calcification was significantly inhibited in SMC-iRNA compared with SMC-CT at all time points examined. Overexpression of Pit-1 restored phosphate uptake and phosphate-induced calcification in Pit-1 deficient cells. Mechanistically, although Pit-1-mediated SMC calcification was not associated with apoptosis or cell-derived vesicles, inhibition of phosphate uptake in Pit-1 knockdown cells blocked the induction of the osteogenic markers Cbfa-1 and osteopontin. Our results indicate that phosphate uptake through Pit-1 is essential for SMC calcification and phenotypic modulation in response to elevated phosphate.

Aorta↗
PubMed2006

Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells.

Apoptosis is essential for the initiation and progression of vascular calcification. Recently, we showed that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors (statins) have a protective effect against vascular smooth muscle cell calcification by inhibiting apoptosis, where growth arrest-specific gene 6 (Gas6) plays a pivotal role. In the present study, we clarified the downstream targets of Gas6-mediated survival signaling in inorganic phosphate (Pi)-induced apoptosis and examined the effect of statins. We found that fluvastatin and pravastatin significantly inhibited Pi-induced apoptosis and calcification in a concentration-dependent manner in human aortic smooth muscle cells (HASMC), as was found with atorvastatin previously. Gas6 and its receptor, Axl, expression were downregulated in the presence of Pi, and recombinant human Gas6 (rhGas6) significantly inhibited apoptosis and calcification in a concentration-dependent manner. During apoptosis, Pi suppressed Akt phosphorylation, which was reversed by rhGas6. Wortmannin, a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor, abolished the increase in Akt phosphorylation by rhGas6 and eliminated the inhibitory effect of rhGas6 on both Pi-induced apoptosis and calcification, suggesting that PI3K-Akt is a downstream signal of the Gas6-mediated survival pathway. Pi reduced phosphorylation of Bcl2 and Bad, and activated caspase 3, all of which were reversed by rhGas6. The inhibitory effect of statins on Pi-induced apoptosis was accompanied by restoration of the Gas6-mediated survival signal pathway: upregulation of Gas6 and Axl expression, increased phosphorylation of Akt and Bcl2, and inhibition of Bad and caspase 3 activation. These findings indicate that the Gas6-mediated survival pathway is the target of statins' effect to prevent vascular calcification.

Androstadienes↗
PubMed2004

Regulatory role of endothelium in the expression of genes affecting arterial calcification.

Vascular calcification is a highly regulated process sharing features of bone mineralization. Since endothelium regulates many of the processes during atherogenesis, we monitored the expression of genes involved in calcification upon exposure of human coronary artery endothelial cells (HCAECs) to atherogenic stimuli. Genes studied were: core binding factor alpha-1 (Cbfa1/Runx2), a pivotal transcriptional regulator of osteogenesis; bone morphogenetic protein-2 (BMP2), an inducer of cartilage and bone; and matrix gla-protein (MGP), a potent inhibitor of calcification, which exerts its action by blocking BMP2. HCAECs were treated with oxidized-low density lipoprotein (ox-LDL, 80 microg/mL) or tumor necrosis factor-alpha (TNFalpha, 10 ng/mL), and the expression of Cbfa1, BMP2, and MGP was quantified by real-time PCR. Cbfa1 was expressed at low levels in untreated HCAECs, and its expression did not change with ox-LDL or TNFalpha treatment. The expression of BMP2 and MGP increased early after exposure to ox-LDL or TNFalpha (at 2-8 h), and the increase was not evident at 24 h. Ox-LDL exerted a stronger effect on MGP than on BMP2 expression. The effects of ox-LDL, but not TNFalpha, on MGP and BMP2 expression were inhibited by pretreatment of cells with an antibody directed at LOX-1, a lectin-like receptor for ox-LDL (10 microg/mL). Thus, the endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory MGP, while the expression of Cbfa1 remains unchanged. Upregulation of BMP2 may represent a feedback upregulation in response to increase in MGP. The effect of ox-LDL appears to be mediated by LOX-1 activation.

Antibodies↗
PubMed2005

Identification and characterization of vascular calcification-associated factor, a novel gene upregulated during vascular calcification in vitro and in vivo.

OBJECTIVE: Vascular calcification, with its increasing clinical sequelae, presents an important and unresolved dilemma in cardiac and vascular practice. We aimed to identify molecules involved in this process to develop strategies for treatment or prevention. METHODS AND RESULTS: Using subtractive hybridization, a novel cDNA, designated vascular calcification-associated factor (VCAF), has been isolated from a bovine retinal pericyte cDNA library generated during the differentiation and mineralization of these cells in vitro. RNA ligase-mediated rapid amplification of cDNA ends was used to compile the 740-bp bovine cDNA sequence. Database searching reveals that VCAF has novel nucleotide/amino acid sequences. RNA analysis confirms that VCAF is upregulated in mineralized pericytes and is present in human calcified arteries but not noncalcified arteries. Protein analysis using a VCAF antibody confirms the presence of an 18-kDa protein in calcified nodules but not in confluent pericytes. Adenoviral antisense VCAF gene delivery reduces VCAF protein levels and accelerates pericyte differentiation compared with controls. CONCLUSIONS: We demonstrate the isolation of a novel gene, VCAF, which is upregulated during vascular calcification in vitro and in vivo. Antisense VCAF gene delivery accelerates pericyte differentiation, implicating a role for VCAF in this clinically significant pathological process.

Adenoviridae↗
PubMed1998

Fibronectin and collagen I matrixes promote calcification of vascular cells in vitro, whereas collagen IV matrix is inhibitory.

Vascular calcification is a frequent component of atherosclerosis, yet the pathological mechanisms that regulate its formation are poorly understood. Calcification of the vessel wall may represent a process by which cells that normally exhibit a smooth muscle phenotype differentiate into cells that exhibit an osteoblast-like phenotype. One of the determinants of cellular phenotype is extracellular matrix; thus, we undertook the current study to evaluate the influence of extracellular matrix on calcification of vascular cells in vitro. Cell lines derived from bovine aortic media were divided into 1 of 3 groups: those that did not mineralize, those that mineralized slowly, or those that mineralized rapidly. When slowly mineralizing cells were plated onto matrix produced by rapidly mineralizing cells, the time required for mineralization decreased from 33+/-3.0 days to 7.8+/-1.3 days. Matrix produced by rapidly mineralizing cells was found to contain 3 times the amount of collagen I and fibronectin but 70% less collagen IV than nonmineralizing clones. When slowly mineralizing cells were cultured on purified collagen I or fibronectin, mineralized nodule formation, calcium incorporation, von Kossa staining, and alkaline phosphatase activity increased. In contrast, culturing slowly mineralizing cells on purified collagen IV inhibited these mineralization parameters. Furthermore, blocking antibodies to alpha5 integrins significantly inhibited the fibronectin-mediated increases in alkaline phosphatase activity, indicating that integrin-based signaling may be involved. These data suggest that matrix composition can regulate development of arterial calcification and that a subpopulation of vascular cells preferentially produces positively regulating matrix components.

Alkaline Phosphatase↗
PubMed2001

Leptin enhances the calcification of vascular cells: artery wall as a target of leptin.

Leptin, the product of the ob gene, regulates food intake, energy expenditure, and other physiological functions of the peripheral tissues. Leptin receptors have been identified in the hypothalamus and in extrahypothalamic tissues. Increased circulating leptin levels have been correlated with cardiovascular disease, obesity, aging, infection with bacterial lipopolysaccharide, and high-fat diets. All these conditions have also been correlated with increased vascular calcification, a hallmark of atherosclerotic and age-related vascular disease. In addition, the differentiation of marrow osteoprogenitor cells is regulated by leptin. Thus, we hypothesized that leptin may regulate the calcification of vascular cells. In this report, we tested the effects of leptin on a previously characterized subpopulation of vascular cells that undergo osteoblastic differentiation and calcification in vitro. When treated with leptin, these calcifying vascular cells had a significant 5- to 10-fold increase in alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells. Prolonged treatment with leptin enhanced the calcification of these cells, further supporting the pro-osteogenic differentiation effects of leptin. Furthermore, the presence of the leptin receptor on calcifying vascular cells was demonstrated using reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blot analysis. We also identified the presence of leptin receptor in the mouse artery wall, localized to subpopulations of medial and adventitial cells, and the expression of leptin by artery wall cells and atherosclerotic lesions in mice. Taken together, these results suggest that leptin regulates the osteoblastic differentiation and calcification of vascular cells and that the artery wall may be an important peripheral tissue target of leptin action.

Alkaline Phosphatase↗
PubMed2006

High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells.

BACKGROUND: Vascular calcification is common in diabetes but the pathogenesis is poorly understood. METHODS: To investigate the pathogenesis, we first examined the histology of inferior epigastric arteries from diabetic and non-diabetic patients undergoing a renal transplant. To examine the role of hyperglycaemia, bovine vascular smooth muscle cells (BVSMCs) were incubated with normal (5 mM) or high glucose (25 mM) for 48 or 72 h. RESULTS: The results demonstrated that diabetic patients, compared with non-diabetic patients, had significantly greater calcification and increased expression of the bone matrix proteins osteopontin, type I collagen, bone sialoprotein and alkaline phosphatase (ALP). The in vitro studies demonstrated that high glucose increased the expression of the osteoblast transcription factor core binding factor alpha subunit 1 (Cbfa1) and its downstream protein osteocalcin by 1.9-fold and 1.8-fold, respectively, and ALP activity by 1.5-fold. These findings were blunted in the presence of an inhibitor to protein kinase C. High glucose also significantly enhanced calcification in BVSMC in a time-dependent manner (2.20 +/- 0.50 vs 1.35 +/- 0.55 micromol/mg, day 7; 5.04 +/- 1.35 vs 3.12 +/- 0.92 micromol/mg, day 14; P < 0.05). High glucose also induced the secretion of bone morphogenetic protein-2, a known osteoinductive factor, and further increased the secretion normally seen during calcification by 43% at day 7 and 57% at day 14. CONCLUSIONS: These results demonstrate that vascular calcification in patients with diabetes is a cell-mediated process characterized by a phenotypic change of VSMCs to osteoblast-like cells with increased bone matrix protein expression, and that hyperglycaemia may directly induce these changes.

Animals↗
PubMed2007

Association of serum fetuin-A with carotid arterial stiffness.

OBJECTIVE: Fetuin-A is a circulating glycoprotein which is well characterized as an inhibitor of ectopic calcification. Vascular calcification commonly found in chronic kidney disease (CKD) patients is a predictor of cardiovascular death. Recently, several groups have demonstrated that low fetuin-A levels are associated with mortality in uraemic patients, possibly through regulation of vascular calcification. However, the physiological significance of fetuin-A in atherosclerosis remains unknown, except in specific conditions, such as vascular calcification in CKD patients. The objective of this study was to investigate the association between serum fetuin-A levels and arterial stiffness, a functional property of atherosclerosis, in healthy subjects. PATIENTS AND MEASUREMENTS: The study subjects comprised 141 healthy subjects. We measured serum fetuin-A levels and stiffness parameter beta for the common carotid artery, which was assessed by ultrasound using a phase-locked echo-tracking system. RESULTS: Simple regression analyses indicated that serum fetuin-A levels were significantly correlated with stiffness parameter beta (r = 0.200, P = 0.018). Multiple regression analyses showed that, besides age, fetuin-A (beta = 0.166, P = 0.033) independently contribute to the stiffness parameter beta (R(2) = 0.310, P < 0.0001). CONCLUSIONS: Serum fetuin-A level is associated with carotid arterial stiffness, independent of known atherogenic factors in healthy subjects.

Age Factors↗
PubMed2001

Biology of calcification in vascular cells: intima versus media.

BACKGROUND: Vascular calcification occurs at two distinct sites within the vessel wall: the intima and the media. Intimal calcification occurs in the context of atherosclerosis, associated with lipid, macrophages and vascular smooth muscle cells, whereas medial calcification can exist independently of atherosclerosis and is associated with elastin and vascular smooth muscle cells. PATHOGENESIS: In this review we compare intimal and medial calcification, particularly discussing the mechanisms which may be responsible for each type of calcification. Similar mechanisms probably initiate and regulate both forms of calcification including the generation of matrix vesicles/apoptotic bodies and local expression of mineralization-regulating proteins. However, since different modifying agents such as lipids in the intima and elastin in the media are present at the sites of calcification and are associated with particular diseases, this implies that the etiologies of these processes differ. For example, intimal calcification is associated with atherosclerosis while medial calcification occurs commonly in the diabetic neuropathic leg. CLINICAL IMPORTANCE: Since both types of calcification correlate with significant morbidity and mortality, we discuss the different types of calcification in terms of their clinical importance.

Adult↗
PubMed2005

Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification.

Vascular calcification predicts an increased risk for cardiovascular events/mortality in atherosclerosis, diabetes, and ESRD. Serum concentrations of alpha(2)-Heremens-Schmid glycoprotein, commonly referred to as fetuin-A, are reduced in ESRD, a condition associated with an elevated circulating calcium x phosphate product. Mice that lack fetuin-A exhibit extensive soft tissue calcification, which is accelerated on a mineral-rich diet, suggesting that fetuin-A acts to inhibit calcification systemically. Western blot and immunohistochemistry demonstrated that serum-derived fetuin-A co-localized with calcified human vascular smooth muscle cells (VSMC) in vitro and in calcified arteries in vivo. Fetuin-A inhibited in vitro VSMC calcification, induced by elevated concentrations of extracellular mineral ions, in a concentration-dependent manner. This was achieved in part through inhibition of apoptosis and caspase cleavage. Confocal microscopy and electron microscopy-immunogold demonstrated that fetuin-A was internalized by VSMC and concentrated in intracellular vesicles. Subsequently, fetuin-A was secreted via vesicle release from apoptotic and viable VSMC. Vesicles have previously been identified as the nidus for mineral nucleation. The presence of fetuin-A in vesicles abrogated their ability to nucleate basic calcium phosphate. In addition, fetuin-A enhanced phagocytosis of vesicles by VSMC. These observations provide evidence that the uptake of the serum protein fetuin-A by VSMC is a key event in the inhibition of vesicle-mediated VSMC calcification. Strategies aimed at maintaining normal circulating levels of fetuin-A may prove beneficial in patients with ESRD.

Blood Proteins↗
PubMed2005

Increased arterial calcification in Paget's disease of bone.

When examining radiographs of patients with Paget's disease of bone (PD), we often observed calcification of the aorta and iliac or femoral arteries. The processes of extraosseous calcification or mineralization are very close to the mechanisms regulating mineralization of bone tissue. The aim of our study was to quantify the number, extent (length and thickness), and type (arteriosclerotic or medial arterial calcification) of vascular calcification in patients with Paget's disease and to compare them with those of controls, in order to discover whether PD is accompanied by increased calcification. Vascular calcification was quantified on the aorta, the iliac arteries, and their branches, the femoral, gluteal, and pelvic arteries of 42 patients with Paget's disease and 36 control subjects. Of the PD subjects, 52.4% had arteriosclerotic calcification versus 30.6% of controls (P = 0.05), and 38.6% of PD patients had medial arterial calcification versus 11.1% of controls (P = 0.05). The mean length of calcification was greater in PD patients: 1.93 +/- 2.85 cm versus 0.84 +/- 1.69 cm in controls (P = 0.04). The thickness of calcification was also greater in PD patients: 1.24 +/- 1.30 mm versus 0.56 +/- 0.94 mm (P = 0.01). Patients with Paget's disease more frequently had medial arterial or arteriosclerotic calcification than controls. These calcifications were longer and thicker. Our clinical study therefore confirms that abnormal vessel wall calcification and bone remodeling in Paget's disease are probably linked, although the mechanism of this relation is as yet unexplained.

Aged↗