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PubMed2006

Molecular mechanisms mediating vascular calcification: role of matrix Gla protein.

Patients with chronic kidney disease (CKD) have a higher incidence of vascular calcification and a greatly increased risk of cardiovascular death. The mechanisms involved in the accelerated vascular calcification observed in CKD have recently become clearer, leading to the hypothesis that a lack of natural inhibitors of calcification may trigger calcium deposition. One of these inhibitory factors, matrix Gla protein (MGP), is the focus of the present review. MGP, originally isolated from bone, is a vitamin K-dependent protein that is also highly expressed by vascular smooth muscle cells. MGP has been confirmed as a calcification-inhibitor in numerous studies; however, its mechanism of action is not completely understood. It potentially acts in several ways to regulate calcium deposition including: (i) binding calcium ions and crystals; (ii) antagonizing bone morphogenetic protein and altering cell differentiation; (iii) binding to extracellular matrix components; and (iv) regulating apoptosis. Its expression is regulated by several factors including retinoic acid, vitamin D and extracellular calcium ions, and a reduced form of vitamin K (KH2) is important in maintaining MGP in an active form. Therefore, strategies aimed at increasing its expression and activity may be beneficial in tipping the balance in favour of inhibition of calcification in CKD.

Calcinosis↗

PubMed2001

[Renal dysfunction and hyperphosphatemia--role of hyperphosphatemia on vascular calcification].

Coronary-artery calcification was present in 14 of 16 hemodialysis patients who were 20 to 30 years old by electron-beam computed tomography. Bone matrix protein, such as osteopontin produced by infiltrating macrophages into the atherosclerotic arterial lesions, is thought to be associated with vascular calcification. Therefore, it is required to recognize the interaction between abnormal bone metabolism and vascular calcification. Control of serum phosphorus levels is likely to be most important for the prevention and treatment of vascular calcification in patients with end-stage renal diseases.

English Abstract↗

PubMed2001

The role of apoptosis in the initiation of vascular calcification.

The initiation sites for calcification in cartilage and bone are cellular products called matrix vesicles. Similar structures have been found in calcified arteries and recent studies suggest that these may be derived from apoptotic cells. It is well established that there is a link between cell death and calcification but the mechanism involved is not known. Since apoptotic cell death is known to occur in the vasculature, we set out to investigate the role of apoptosis in the initiation of vascular calcification. We used a human vascular calcification model in which postconfluent vascular smooth muscle cell (VSMC) cultures form nodules spontaneously and calcify after approximately 28 days. Our studies revealed that apoptosis occurred prior to the onset of calcification and that VSMC "blebs" or apoptotic bodies (ABs) could concentrate calcium in a crystallised form. These observations suggest that apoptosis is involved in the development of VSMC calcification and that VSMC-derived ABs have similarities with matrix vesicles.

Apoptosis↗

PubMedDate not supplied

Vascular calcification in end-stage renal disease.

Vascular calcification is common in patients with end-stage renal disease (ESRD) who are treated with regular dialysis, and it may contribute to the very high mortality rate from cardiovascular causes in such patients. Arterial calcification in those with chronic renal failure can result from the deposition of mineral along the intimal layer of arteries in conjunction with atherosclerotic plaques or from calcium deposition in the medial wall of arteries that is due, at least in part, to disturbances in mineral metabolism. Several reports indicate that coronary artery calcification as measured by electron-beam computed tomography (EBCT) is common and often quite extensive in patients with ESRD, but the clinical significance of this finding remains uncertain. EBCT measurements of coronary artery calcification have been shown to be a useful marker of atherosclerotic burden in the general population, and values serve to predict the risk of adverse cardiovascular events. By contrast, the relationship between coronary artery calcification scores as measured by EBCT and clinically significant coronary artery lesions has not been studied adequately in patients with ESRD. Indeed, calcium accumulation in the coronary arteries and other systemic vessels in patients with chronic renal failure is probably attributable to both intimal and medial wall calcification. Concurrent assessments using coronary angiography and EBCT are needed to determine the diagnostic value of EBCT as a predictor of cardiovascular disease in patients with ESRD. Despite the shortcomings of currently available data, the technique of EBCT makes it possible to detect the presence and to monitor the progression of coronary calcification in those undergoing long-term dialysis. Studies using this non-invasive diagnostic method may provide important new information about factors that initiate the development and mediate the progression of arterial calcification in patients with ESRD.

Calcinosis↗

PubMed2005

Ethiopathogenesis, diagnosis and prevention of vascular calcification in end stage renal disease.

Extensive atherosclerosis and heavy vascular and valvular calcifications are common complications of end stage renal disease (ESRD) and are very likely related to the high incidence of cardiovascular disease in these patients. The greatly increased incidence of cardiovascular disease is only partly explained by traditional risk factors for atherosclerosis. In ESRD, vascular calcification occurs both in the vascular intima layer and in the tunica media. Intimal calcification is disseminated and is characteristically associated with damaged and abnormally functioning endothelium, and macrophage and vascular smooth muscle cell (VSMC) infiltration typical of atherosclerosis. On the contrary, medial calcification occurs in patchy distribution and the most frequent cell types found in its vicinity are the VSMC and macrophage. The uremic state is associated with numerous metabolic abnormalities and endocrine disturbances primarily involving calcium and phosphorus metabolism. Furthermore, chronic kidney disease and dialysis are considered states of active and strong inflammatory response. These dysfunctions occur early in the course of renal failure and likely contribute to the development and progression of vascular calcification and atherosclerosis. For many years, vascular calcification was considered solely the result of a passive deposition of hydroxyapatite crystals in the arterial wall due to elevated calcium-phosphate ion product. However, a large body of evidence has now shown that this is a highly regulated process governed by factors that closely resemble calcium deposition in bone tissue. In fact, vascular calcification requires changes in the phenotype of VSMC and the expression of several proteins normally involved in bone metabolism. This review is centered on the etiopathogenesis of vascular calcification in ESRD, its detection with modern imaging modalities and the therapeutic approaches currently available to slow its progression.

Calcinosis↗

PubMed2005

[Pharmacologic intervention for vascular calcification].

In patients with chronic renal insufficiency and dialysis, phosphate retention is a major factor in the development of vascular calcification. Prevention of phosphate retention with dietary and pharmacological means may prevent vascular calcification. Current therapy for hyperphosphatemia includes the administration of phosphate binders such as calcium carbonate (or calcium acetate), ammonium-based compounds, and phosphate-binding polymers (Renagel; sevelamer hydrochloride). However, it is difficult to administrate present phosphate binders to patients because of hypocalcaemia, outright toxicity, and constipation as its side effect. It is needed to development new drugs having fewer side effects and better compliance.

Calcinosis↗

PubMed2005

Vascular calcification.

PURPOSE OF REVIEW: Accumulating evidence suggests that the high cardiovascular mortality observed in patients with end-stage renal disease is due in part to the deleterious effects of vascular calcification that develops over time on dialysis. This review focuses on recent cell biological and animal studies that have shed light on the mechanisms and regulators of vascular smooth muscle cell calcification in end-stage renal disease. RECENT FINDINGS: Clinical studies demonstrate that high circulating levels of phosphate or calcium predict vascular calcification. Recent cell biological studies have provided novel insights into how vascular smooth muscle cells regulate calcification in response to such insults. Vascular smooth muscle cell damage and subsequent vesicle release from viable and dying cells create an environment permissive for the nucleation of basic calcium phosphate mineral. This, combined with osteogenic conversion of vascular smooth muscle cells and consequent loss of their normal inhibitory processes/pathways, results in calcification. Circulating factors such as fetuin-A, with the potential to impact on vessel wall calcification, have also been identified. Animal studies suggest that the 'uremic milieu' potentiates calcification and have clearly established a link between vascular calcification and bone metabolism. However, our understanding of the factors that contribute to vascular smooth muscle cell calcification in end-stage renal disease remains incomplete. SUMMARY: Systematic studies are required that integrate epidemiological studies to identify risk factors with in-vitro experiments to investigate mechanisms leading to vascular smooth muscle cell calcification in response to these factors. Animal and clinical studies can subsequently be used to assess how modifying risk factors under the complex physiological conditions of end-stage renal disease impacts on vessel wall health.

Animals↗

PubMed2002

Monocyte/macrophage regulation of vascular calcification in vitro.

BACKGROUND: Calcification is a common complication of atherosclerosis and other chronic inflammatory processes that involves infiltration of monocytes and accumulation of macrophages. METHODS AND RESULTS: To determine whether these cells modulate vascular calcification in vitro, calcifying vascular cells (CVCs), a subpopulation of osteoblast-like cells derived from the artery wall, were cocultured with human peripheral blood monocytes for 5 days. Results showed that alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation, was significantly greater in cocultures than in cultures of CVCs or monocytes alone. Both ALP activity and matrix mineralization increased in proportion to the number of monocytes added. Activation of monocyte/macrophages (M/Ms) by oxidized LDL further increased ALP activity in cocultures. However, neither conditioned medium from oxidized-LDL-activated M/Ms or transwell coculture had this effect on CVCs, which suggests a need for cell-to-cell contact. In contrast, conditioned medium from lipopolysaccharide-activated M/Ms increased ALP activity of CVCs. ELISA showed that lipopolysaccharide-activated M/Ms secreted tumor necrosis factor-alpha, and neutralizing antibody to tumor necrosis factor-alpha attenuated the induction of ALP activity by the conditioned media. CONCLUSIONS: These results suggest that M/Ms enhance in vitro vascular calcification via 2 independent mechanisms: cell-cell interaction and production of soluble factors such as tumor necrosis factor-alpha.

Alkaline Phosphatase↗

PubMed1999

[Vascular calcification after kidney transplantation. Preliminary results].

BACKGROUND: Vascular calcifications (VC) are a common feature in chronic dialysis patients, but their clinical significance is debated, and the role of kidney transplantation (TRP) in the natural history of their development has received only scanty attention. METHODS: In our study we reviewed skeletal surveys as well as clinical and biochemical records of 13 patients who started again chronic dialysis at our Centre after failure of their kidney grafts. Changes of VC (during TRP) were scored as: 1 = no substantial progression (4 patients), 2 = moderate worsening (4 patients), 3 = severe worsening (5 patients = 38.4%). RESULTS: The most interesting association with the clinical/biochemical parameters seems to be between the score 3 subgroup and highest Ca*P values and vitamin D therapy. Four out of five score 3 patients experienced overt vascular events and 4 out of 5 of the same subgroup experienced parathyroidectomy (PTX) before, during or after the TRP. CONCLUSIONS: In this preliminary study we can conclude that a) the possibility of dramatic worsening of VC during TRP is not a rare event and this feature has a strong clinical implication, b) PTX before TRP could remove at least one of the putative risk factors in patients waiting for TRP with suboptimal control with medical therapy.

Adolescent↗

PubMed2005

Clinical impact of preexisting vascular calcifications on mortality after renal transplantation.

BACKGROUND: Vascular calcifications (VC) are a well-known cardiovascular risk factor (CVRF) in uremic patients. However, their role on mortality after renal transplantation (RT) is unclear. METHODS: In 1117 RT recipients, we investigated the association between long-term survival and the presence of VC, evaluated by preoperative posteroanterior plain radiography from aorto-iliac region, at the time of RT. The primary study outcome was all-cause mortality. Other perioperative CVRF were also collected. RESULTS: VC were observed in 273 patients (24.4%) before RT; additionally, 132 (12%) patients died during follow-up, due, mainly, to cardiovascular (39%) or infectious (24%) complications. As expected, patients with VC showed a higher age and a greater number of CVRF than those without VC. Overall mortality rate was also higher in VC group (19 vs. 9.5%; P= 0.0001), as well as cardiovascular mortality (9.5 vs. 3.1; P= 0.048). Multivariate Cox model showed that VC were predictor of overall mortality [relative risk (RR) 1.8; 95% CI 1.1-2.8; P= 0.015] and cardiovascular mortality (RR 2.6; 95%CI 1.1-6); P= 0.033), independently of other CVRF. An interaction between the presence of VC and diabetes was found. The effect of VC on mortality was evident in nondiabetic patients, that is, those with VC had a significantly higher mortality rate than patients without VC (21 vs. 9%; P= 0.0001). By contrast, these differences were not observed in diabetic patients (16.5 vs. 14.3%; P= 0.656). CONCLUSION: VC evaluated by a simple and inexpensive plain radiography are an independent predictor of cardiovascular and all-cause mortality following RT. This finding may encourage the implementation of appropriate therapeutic strategies after RT.

Adult↗

PubMed2002

[Vitamin K and vascular calcification].

Until recently, vitamin K has been exclusively related to blood coagulation. During the last decade, a second function for vitamin K-dependent proteins has become apparent : the regulation of tissue calcification. One of them is the function of Matrix Gla Protein (MGP) : potent inhibitors of vascular calcification. The function of MGP became clear from transgenic mice (MGP-deficient mice). Further research on MGP will resolve the complicated mechanism of atherosclerosis, especially of the arterial calcification. The recommended daily allowance for vitamin K to prevent vascular calcification should be evaluated.

English Abstract↗

PubMed2005

Ghrelin blunted vascular calcification in vivo and in vitro in rats.

Ghrelin is a new peptide with regulatory actions in growth hormone secretion in the anterior pituitary gland and in energy metabolism. Currently, ghrelin has potently protective effects in cardiovascular diseases. We used an in vivo model of rat vascular calcification induced by vitamin D3 and nicotine and one of cultured rat vascular smooth muscular cells (VSMCs) calcification induced by beta-glycerophosphate to study the possible mechanism in the regulatory action of ghrelin in vascular calcification. Calcification increased total Ca2+ content and 45Ca2+ deposition in aortas and VSMCs and alkaline phosphatase (ALP) activation in plasma, aortas and VSMCs. However, calcified aortas and VSMCs showed a significant decrease in osteopontin (OPN) mRNA expression and a marked reduction of ghrelin levels in plasma and its mRNA expression in aortas. The aortic calcification was significantly attenuated by subcutaneous administration of ghrelin 30 and 300 nmol kg(-1) day(-1) for 4 weeks, and the latter dosage was more potent than the former. Ghrelin treatment at the two dosages reduced the total aorta Ca2+ content by 24.4% and 28.1%, aortic 45Ca2+ deposition by 18.4% and 24.9%, plasma ALP activity by 36.6% and 76.7%, and aortic ALP activity by 10.3% and 47.6% (all P < 0.01 or 0.05), respectively. Ghrelin at 10(-8)-10(-6) mol/L attenuated the calcification in cultured VSMCs, with decreased total Ca2+ content, 45Ca2+ deposition and ALP activity and increased OPN mRNA expression, in a concentration-dependent manner. In addition, endothelin levels in plasma and aortas and its mRNA expression in aortas significantly increased with calcification, but ghrelin treatment significantly decreased endothelin levels and mRNA expression, with the high dosage being more potent than the lower dosage. These results indicate that local ghrelin in vascular was down-regulated during vascular calcification, whereas administration of ghrelin effectively attenuated vascular and VSMCs calcification.

Animals↗

PubMedDate not supplied

Intracranial vascular calcifications mimicking small saccular aneurysms on CT angiography: a technical note and case description.

The authors describe a case of intracranial vascular calcifications that mimicked small saccular aneurysms on CT angiography (CTA). The density of two vascular calcifications was visually similar to that of contrast in the parent vessel, making them indistinguishable from aneurysmal outpouchings. Comparison of the CTA with the non-contrast head CT (NCCT) was critical to distinguish low-density calcifications from tiny aneurysms.

Calcinosis↗

PubMed2005

Vascular calcifications in chronic kidney disease: are there new treatments?

Cardiovascular disease is extremely common in patients with end-stage renal disease (ESRD) and accounts for at least 50% of deaths among these patients. Vascular calcifications (VC) have been recently implicated as a possible cause of this excess cardiovascular mortality. Medial calcification is a striking feature of vascular disease in patients with ESRD. The traditional view that VC is a degenerative and passive process has been seriously challenged, based on strong evidence suggesting that VC is an active and highly regulated process similar to bone formation. Different data support the notion that elevated levels of phosphorus and/or other uremic toxins may play an important role by transforming vascular smooth muscle cells into osteoblast-like cells, which can produce bone matrix proteins. This nidus can then mineralize if the balance of pro-mineralizing factors outweighs inhibitory factors. The advent of newer noninvasive screening tests have generated great interest for screening patients with ESRD for vascular calcifications. Control of serum phosphorus with sevelamer, a recently developed non-calcium, non-aluminum phosphate binder, have attenuated or arrested progression of coronary artery and aortic calcifications compared to treatment with calcium-based binders. Amino bisphosphonates, have shown to completely inhibit soft tissue calcifications, calciphylaxis and prevent death in animal models. The first generation bisphosphonate, etidronate, reduces the progression of coronary artery calcifications patients receiving long-term hemodialysis and intravenous pamidronate has produced a rapid improvement of calciphylaxis. In conclusion, VC is a widespread phenomenon in patients with ESRD with important cardiovascular consequences. A better understanding of the processes of VC is leading to therapies to retard or improve this phenomenon and will probably have an important impact on patient mortality.

Animals↗

PubMed2004

Determinants of progressive vascular calcification in haemodialysis patients.

BACKGROUND: We determined recently that targeted treatment with calcium-based phosphate binders (calcium acetate and carbonate) led to progressive coronary artery and aortic calcification by electron beam tomography (EBT), while treatment with the non-calcium-containing phosphate binder, sevelamer, did not. Aside from the provision of calcium, we hypothesized that other factors might be related to the likelihood of progressive calcification in both or either treatment groups. METHODS: We explored potential determinants of progressive vascular calcification in 150 randomized study subjects who underwent EBT at baseline and at least once during follow-up (week 26 or 52). RESULTS: Among calcium-treated subjects, higher time-averaged concentrations of calcium, phosphorus and the calcium-phosphorus product were associated with more pronounced increases in EBT scores; no such associations were demonstrated in sevelamer-treated subjects. The relation between parathyroid hormone (PTH) and the progression of calcification was more complex. Lower PTH was associated with more extensive calcification in calcium-treated subjects, whereas higher PTH was associated with calcification in sevelamer-treated subjects. Serum albumin was inversely correlated with progression in aortic calcification. Sevelamer was associated with favourable effects on lipids, although the link between these effects and the observed attenuation in vascular calcification remains to be elucidated. CONCLUSION: Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification, especially when mineral metabolism is not well controlled. Calcium may directly or indirectly (via PTH) adversely influence the balance of skeletal and extraskeletal calcification in haemodialysis patients.

Aged↗

PubMed2001

Vascular calcification: expression patterns of the osteoblast-specific gene core binding factor alpha-1 and the protective factor matrix gla protein in human atherogenesis.

OBJECTIVE: Increasing evidence suggests that vascular calcification is a regulated process. We studied the vascular expression pattern of a key factor in mineralization and a counteracting, protective factor. Based on the phenotype of null mice, Core binding factor alpha-1 (Cbfa-1) plays a pivotal role in bone formation, whereas Matrix Gla Protein (MGP) is a potent inhibitor of vascular calcification. METHODS: We investigated the expression of MGP and Cbfa-1 in cultured, human monocytic cells, endothelial cells and smooth muscle cells (SMC), as well as in normal and atherosclerotic vessel specimens. RESULTS: In cultured cells MGP is expressed in endothelial cells and SMC, whereas Cbfa-1 mRNA is predominantly present in macrophages and to a lesser extent in SMC. In the normal vessel wall MGP expression is high at the luminal side and declines toward the center of the media, whereas Cbfa-1 is absent. Moderate, diffuse calcification of the aorta media was observed only in those regions where MGP is low or absent. In atherosclerotic lesions MGP is expressed in endothelial cells and SMC that form fibrous caps, but is never present in macrophages. Cbfa-1 is synthesized in regions without MGP, it is associated with calcified areas and Cbfa-1 may be considered a marker for osteoprogenitor-like cells in the vessel wall. CONCLUSIONS: Our observations on MGP expression confirm and extend published data and are consistent with a protective function of MGP. Cbfa-1 expression is absent in normal medial SMC and co-localizes with neointimal macrophages and focal calcifications.

Arteriosclerosis↗

PubMed2004

Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients.

BACKGROUND: 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. METHODS: Serum OPG was measured in 102 patients who were undergoing haemodialysis. The aortic calcification index (ACI) was assessed by computed tomography scans. RESULTS: 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). CONCLUSIONS: 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.

Adult↗

PubMed1998

Expression of matrix Gla protein (MGP) in an in vitro model of vascular calcification.

To investigate the role of matrix Gla protein (MGP), which can bind mineral ions through gamma-carboxylated glutamic acid residues, in vascular calcification, we examined the expression of MGP in an in vitro calcification model by using bovine vascular smooth muscle cells (BVSMC). The expression of MGP mRNA was decreased during BVSMC calcification and its levels were inversely correlated with the quantities of BVSMC calcification. MGP mRNA expression was restored to the level of uncalcified control by inhibiting BVSMC calcification with bisphosphonates. These data suggest that the expression of MGP gene is modulated in the development of vascular calcification.

Alendronate↗