Vascular smooth muscle cells and calcification in atherosclerosis

Trion, Astrid; Laarse, Arnoud van der

doi:10.1016/j.ahj.2003.10.047

Cited by 150 publications

(126 citation statements)

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“…Our results demonstrated that expression of Cbfa-1 and OPN in VSMCs was upregulated after stimulation with elevated Pi and BMP-2, and this was consistent with the observed calcification, as the expression of Cbfa-1 and OPN in SMCs usually serve as markers of osteochondrogenic phenotype transition (16,17). Thus, elevated Pi and BMP-2 may induce SMCs to transition to an osteoblast-like phenotype, and this may contribute to cell calcification.…”

Section: Discussionsupporting

confidence: 73%

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Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro

Huang

Zheng

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. The aim of this study was to explore the effects of the bisphosphonate zoledronate on calcification induced by inorganic phosphate (Pi) and/or bone morphogenetic protein 2 (BMP-2) and the underlying mechanisms. Primary vascular smooth muscle cells (VSMCs) from rats were treated with 3 mM Pi or 3 mM Pi/BMP-2, with and without addition of zoledronate; 1.4 mM Pi served as a control. Calcium deposits, expression of core binding factor α-1 (Cbfa-1), osteopontin (OPN), parathyroid pituitary-specific transcription factor (Pit)-1 and Pit-2, and Pi uptake of VSMCs was determined. The calcification of VSMCs induced by elevated Pi or Pi/ BMP-2 was significantly inhibited by zoledronate. The expression of Cbfa-1, OPN and Pit-1 was increased significantly after treatment with an elevated level of Pi or Pi/BMP-2, and this expression was significantly suppressed by addition of zoledronate. Pi uptake of VSMCs increased following treatment with elevated Pi and significantly decreased by addition of zoledronate. These results indicated that zoledronate effectively inhibited calcification induced by Pi/BMP-2, and this may have been achieved by means of the downregulation of expression of calcification-related proteins and uptake of Pi. IntroductionVascular calcification is highly prevalent and is a major contributor to cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Susceptibility to vascular calcification is in part genetically determined and actively regulated by diverse inducers and inhibitors. One of these inducers, hyperphosphatemia, promotes vascular calcification, and the control of arterial calcification is now recognized as a means to prevent CVD events in patients with CKD (1,2).Vascular calcification is an active, cell-mediated process that results from an imbalance between the promoters and inhibitors of mineralization (3,4). Several molecules that normally regulate osteoblast differentiation and bone formation have been found in calcifying vessels, such as osteonectin, osteocalcin, matrix Gla protein and bone morphogenetic protein 2 (BMP-2) (5-7). Elevated phosphate (Pi) levels also induce smooth muscle cell (SMC) calcification and osteogenic phenotypic modulation (8,9).Bisphosphonates (BPs) are widely used in the treatment of diseases associated with excessive osteoclast-mediated bone resorption, such as osteoporosis (10,11). The classical pharmacological effects of BPs appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs, and this may influence their differential distribution within bone, their biological potency and their duration of action (12,13). It is reported that ibandronate prevents experimentally induced arterial calcification in uremic rats (14). These findings extend the link between bone remodeling and vascular calcification of CKD, opening perspectives toward novel therapeutic strategies. However, whether zoledronate, a new third generati...

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Section: Discussionsupporting

confidence: 73%

“…Expression of BMP-2 is also found in calcified human atherosclerotic lesions (7,8). In addition, treatment of calcifying vascular or SMCs in vitro with BMP-2 results in enhanced calcification (15,16). Thus, BMP-2 may play an important role in the regulation of bone formation as well as vascular calcification under conditions of high Pi.…”

Section: Discussionmentioning

confidence: 92%

Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro

Huang

Zheng

et al. 2012

Experimental and Therapeutic Medicine

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“…6 -8 Phosphorus has been further implicated as a cause of VC through studies in vitro that have demonstrated that it induces phenotypic changes in vascular smooth muscle cells (VSMC) by increasing gene transcription of proteins involved in osteoblast function-bone formation 9 and stimulating matrix mineralization. 10 -12 In the uremic calcifying environment, expression of the contractile proteins of VSMC, such as ␣-smooth muscle actin, SM22, and heavy-chain myosin, are suppressed, 13 whereas osteoblastic lineage markers such as osteocalcin, osteopontin, and the bone morphogenetic proteins 2 and 4 (BMP-2 and -4) are increased. 9,14 -16 Furthermore, the osteoblast specific transcription factor RUNX2, which directs skeletal bone formation, 17 is expressed in the vasculature of patients with end-stage CKD.…”

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confidence: 99%

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Mathew¹,

Tustison²,

Sugatani³

et al. 2008

Journal of the American Society of Nephrology

210

171

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Hyperphosphatemia and vascular calcification have emerged as cardiovascular risk factors among those with chronic kidney disease. This study examined the mechanism by which phosphorous stimulates vascular calcification, as well as how controlling hyperphosphatemia affects established calcification. In primary cultures of vascular smooth muscle cells derived from atherosclerotic human aortas, activation of osteoblastic events, including increased expression of bone morphogenetic protein 2 (BMP-2) and the transcription factor RUNX2, which normally play roles in skeletal morphogenesis, was observed. These changes, however, did not lead to matrix mineralization until the phosphorus concentration of the media was increased; phosphorus stimulated expression of osterix, a second critical osteoblast transcription factor. Knockdown of osterix with small interference RNA (siRNA) or antagonism of BMP-2 with noggin prevented matrix mineralization in vitro. Similarly, vascular BMP-2 and RUNX2 were upregulated in atherosclerotic mice, but significant mineralization occurred only after the induction of renal dysfunction, which led to hyperphosphatemia and increased aortic expression of osterix. Administration of oral phosphate binders or intraperitoneal BMP-7 decreased expression of osterix and aortic mineralization. It is concluded that, in chronic kidney disease, hyperphosphatemia stimulates an osteoblastic transcriptional program in the vasculature, which is mediated by osterix activation in cells of the vascular tunica media and neointima. Chronic kidney disease (CKD) is a fatal illness, and cardiovascular complications are the major causes of morbidity and mortality. 1,2 The causes of the excess cardiovascular mortality associated with CKD are unknown, because the role of the standard risk factors associated with cardiovascular mortality do not account for the increased risk in CKD. 2 There is strong epidemiologic evidence that serum phosphorus is an independent risk factor for cardiovascular events and mortality in CKD. 3,4 The serum phosphorus has been linked to another cardiovascular risk factor, vascular calcification (VC), 3,5,6 an important cause of vascular stiffness in CKD leading to increased pulse wave velocity, increased cardiac work, left ventricular hypertrophy, and decreased coronary artery blood flow. 6 -8 Phosphorus has been further implicated as a cause of VC through studies in vitro that have demonstrated that it induces phenotypic changes in vascular smooth muscle cells (VSMC) by increasing gene transcription of proteins involved in osteoblast function-bone formation 9 and stimulating matrix mineralization. 10 -12 In the uremic calcifying environment, expression of the contractile proteins of VSMC, such as ␣-smooth muscle actin, SM22,

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“…[2][3][4] Proteins primarily involved in the regulation of bone mineralization, such as osteocalcin (OC) or osteonectin (ON), have also been linked to local extraosseous regulation of calcium homeostasis. 5 Among all, MGP is considered the key physiological inhibitor of soft tissue calcification, acting as a direct inhibitor of calcium crystal formation, as MGP-deficient mice suffer from spontaneous and ultimately fatal calcification of arteries and cartilage. 6 Together with OC and the clotting factors II, VII, IX, and X, MGP needs to undergo carboxylation of glutamate (Glu) into g-carboxyglutamate (Gla) residues to become active.…”

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confidence: 99%

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

Vanakker

Martin

Schurgers

et al. 2010

Laboratory Investigation

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Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.

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Vascular smooth muscle cells and calcification in atherosclerosis

Cited by 150 publications

References 43 publications

Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro

Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

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