Atherosclerosis and Lipoproteins |
From the Departments of Pathology (C.R.D., J.P.M.C., E.L., K.B.J.M.C., M.J.A.P.D.), Vascular Surgery (P.J.E.H.M.K., J.H.M.T.), and Biochemistry (H.M.H.S., C.V.), Cardiovascular Research Institute Maastricht, University of Maastricht, and Department of Rheumatology (P.P.M.G.), University Hospital Maastricht, Maastricht, Netherlands.
Correspondence to M.J.A.P. Daemen, MD, PhD, Department of Pathology, CARIM, University of Maastricht, PO Box 616, 6200 MD Maastricht, Netherlands. E-mail MDA{at}lpat.azm.nl
| Abstract |
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Key Words: bone matrix proteins atherosclerosis vascular calcification osteogenesis osteoclastogenesis
| Introduction |
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Several proteins are involved in the regulation of skeletal bone formation, such as matrix Gla protein (MGP), osteocalcin (OC; also called bone Gla protein), bone sialoprotein (BSP),12 bone morphogenetic protein-2 and -4 (BMP-2, BMP-4), osteopontin (OPN), and osteonectin (ON). Although the immunolocalization of some of these proteins in the human vessel wall has been described, the available data are rather incomplete and restricted to advanced stages of atherosclerosis. Immunoreactivity of 2 proteins involved in osteoclastogenesis, osteoprotegerin (OPG) and its ligand, OPGL, also named RANKL (receptor activated nuclear factor-kappa B ligand), has not been described before in the human atherosclerotic vessel wall.
In the present study, we examined the protein expression pattern of 7 regulators of bone formation and 2 modulators of osteoclastogenesis in all stages of human atherosclerotic lesions to provide an inventory of the expression of regulators of bone turnover in human atherogenesis.
| Methods |
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Plaque subtypes (5 to 8 per subgroup) were determined according to the classification proposed by Virmani et al.13 Lesion morphology was evaluated on hematoxylin-and-eosinstained sections.
Calcification
Von Kossa staining was used to assess calcification in specimens from all stages of plaque development. This staining was performed by the standard procedure.
Western Blotting
Validation of all antibodies occurred by Western blotting. Proteins were isolated by the urea method (Ready Prep Sequential Extraction Kit, Instruction Manual, Bio-Rad Laboratories). A 15% SDS-PAGE gel with 50 µg of whole cell extract protein per sample was electrophoresed. Proteins were transferred to a nitrocellulose membrane at 30 V. After 1 hour of blocking with 3% bovine serum albumin (Sigma-Aldrich) in 10 mmol/L Tris-buffered saline, pH 7.5, 100 mmol/L NaCl, and 0.1% Tween, blots were incubated with antibodies directed to either MGP (1:200),14 OC (1:800, Anawa Trading SA, Wangen), BSP (1:500),15 BMP-2 (1:350, Santa Cruz Biotechnology, Inc), BMP-4 (1:350, Santa Cruz Biotechnology, Inc), OPN (1:500),15 ON (1:1000, Zymed Laboratories, Inc),16 OPG (1:1000), or OPGL (1:1000). Anti-mouse horseradish peroxidase (HRP; 1:1000, Dako), anti-rabbit HRP (1:2000, Cell Signaling Technology, a New England Biolabs company), and anti-goat HRP (1:2500, Dako) were used as the secondary antibodies. Specific antibody binding was visualized with enhanced chemiluminescence Western blotting detection reagents (Amersham Pharmacia Biotech Benelux).
Immunohistochemical Staining
Paraffin sections (4 µm) were deparaffinized and washed 3 times in Tris-buffered saline (5 mmol/L Tris-HCl, pH 7.5, 140 mmol/L NaCl). Parallel sections were stained with mouse monoclonal antibodies against MGP (1:25) and BMP-2 (1:20, Genetics Institute, Inc); goat polyclonal antibodies against BMP-4 (1:25), OPN (1:125), OPG (1:100), and RANKL/OPGL (1:75); and rabbit polyclonal antibodies against OC (1:50), ON (1:400), and BSP (1:25). For the mouse monoclonal antibodies, biotinylated sheep anti-mouse IgG (1:250, Amersham Life Science) was used as the secondary antibody, whereas biotinylated rabbit anti-goat IgG (1:200, Dako) or sheep anti-rabbit IgG (1:1000, Dako) was used as secondary antibody for the polyclonal antibodies. After incubation with an alkaline phosphatasecoupled avidin-biotin complex (ABC complex, Dako), antibodies were visualized with an alkaline substrate kit (Vector SK-5100, Vector Laboratories, Inc). Sections were counterstained with hematoxylin and mounted with coverslips. In negative controls, incubation with primary antibody was omitted. Because immunohistochemical results of specimens derived from autopsy and surgery did not differ, the data are presented as one group.
In Situ Hybridization
Sense and antisense digoxigenin-labeled RNA probes for MGP, BMP-2, BMP-4, OPN, and ON mRNAs were transcribed from the T7 promoter of pGEM3Z. Hybridization of 4-µm paraffin-embedded sections and visualization with alkaline phosphatasecoupled anti-digoxigenin antibodies and indolylphosphate-nitroblue tetrazolium (BCIP/NBT) substrate were performed as described previously.17 Parallel sections were hybridized with antisense and sense probes. In the negative controls, the probe was not added to the hybridization mixture.
| Results |
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Human heart, liver, and lung tissue were used as negative controls for immunohistochemistry of antibodies directed to MGP, OC, and BSP (Figure II, please see www.atvb.ahajournals.org). MGP was absent in the hepatocytes, but the vessels in the liver did contain MGP. OC and BSP were absent in human heart. Pretreatment of calcified control sections with 3% citric acid resulted in an equal pattern of protein localization as nonpretreated sections, which indicates the lack of aspecific binding of the antibodies to calcium deposits.
Nondiseased Aorta
Five bone matrix proteins (MGP, OC, BSP, BMP-4, and OPG) were present in the nondiseased aorta (Figure III, please see www.atvb.ahajournals.org). MGP (Figure 1A) and BSP were present throughout the intima and media, including in endothelial cells, smooth muscle cells (SMCs), and elastic fibers. BMP-4, ON, and OPG proteins were highly expressed, but only in medial SMCs. OPGL immunoreactivity was very weak and was confined to medial SMCs, a pattern that was comparable to OPG. OC, which, like MGP, is a Gla-containing protein, was only expressed in the endothelial cells lining the lumen. Two bone matrix proteins, BMP-2 and OPN (Figure 1B), were absent in the nondiseased aorta.
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The adventitia showed immunoreactivity for 6 bone matrix proteins: MGP, OC, BSP, BMP-2, BMP-4, and ON. MGP, BSP, and ON were present in adventitial vessels, OC throughout the entire adventitia except for the vessels, and BMP-2 and BMP-4 only in polymorphonuclear cells.
Intimal Xanthoma or Fatty Streak
Characteristic of this type of early lesion is the accumulation of macrophage-derived lipid-filled foam cells in the intima (Figure III). In intimal xanthoma lesions, MGP, BSP, BMP-4, and ON expression was localized in medial SMCs. The intima showed immunoreactivity of 6 bone matrix regulatory proteins. MGP and BSP were present in intimal SMCs. Macrophage-derived lipid-filled foam cells expressed MGP, BSP (Figure 1C), and OC protein, whereas BMP-2, BMP-4 (Figure 1D), OPN, ON, OPG, and OPGL were absent. Endothelial cells lining the lumen expressed OC, BMP-4, OPG, and OPGL.
Fibrous Cap Atheroma
The fibrous cap atheroma is a type of lesion in which a collagenous-proteoglycan matrixcontaining fibrous cap covers the large lipid core (Figure III). Cells present in these lesions include SMCs in the shoulder region of the plaque, foam cells, T cells, and endothelial cells.
Medial SMCs underlying the fibrous cap atheroma showed expression of MGP, BSP, and ON. All 9 proteins investigated showed immunoreactivity in the intima of these lesions. However, localization of the proteins was diverse. BSP, BMP-2, BMP-4 (Figure 1E), ON, and OPG were expressed by the intimal SMCs present in the shoulder regions. Expression of MGP, BSP, OC, BMP-4, OPN, and ON was prominent in foam cells in the lipid core. Some specimens contained cells that can best be described as chondrocyte-like cells that reside in small spaces in the intercellular substance. These cells were mainly localized at the borders of the lipid core and showed high expression of MGP and ON protein (Figure 1F) and moderate BSP and BMP-4 immunoreactivity.
Fibrocalcific Plaque
This type of advanced atherosclerotic plaque is collagen rich, with large areas of calcification and a necrotic core. Together with areas of calcification, we observed cortical bone structures and cells involved in bone turnover, namely, chondrocyte-like cells, osteoblasts, osteocytes, and osteoclasts (Figure III). All bone matrix proteins examined in the present study were highly expressed in these fibrocalcific lesions. As in the fibrous cap atheroma, medial SMCs underlying the fibrocalcific plaque only showed expression of MGP, BSP, and ON, whereas intimal SMCs expressed MGP, BSP, BMP-2, BMP-4, ON, and OPG. CD68-positive macrophages surrounding the necrotic core showed immunoreactivity of MGP, OC, BSP, BMP-4, OPN, and ON. Two types of calcified structures were present in these lesions: calcium mineral deposits and lamellar bone. Around calcium mineral deposits, MGP (Figure 2A) and OPN (Figure 2B) were highly expressed, whereas in the deposits, BSP, OC, BMP-2 (Figure 2C), BMP-4, OPN, and ON showed immunoreactivity. Lamellar bone structures, recognized by the presence of cement lines and osteocytes within bone and osteoblasts lining the bone, showed immunoreactivity of OPN (Figure 2D) and ON. BSP, BMP-2, BMP-4, OPN, ON, and OPG (Figure 2E) lined the bone structures. OC was the only protein present throughout the bone matrix (Figure 2F). OPGL could only be demonstrated in association with the extracellular matrix surrounding calcium deposits (Figure 2G). High expression of BSP, ON, and OPG was seen in the few inflammatory cells present in these fibrocalcific plaques. ON was also highly expressed in the matrix vesicles present in these lesions (Figure 2H).
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In Situ Hybridization
In situ hybridization revealed that MGP mRNA expression pattern colocalizes with the protein. In intimal xanthoma, medial vascular SMCs adjacent to the adventitia expressed MGP mRNA, whereas in fibrocalcific plaques, MGP mRNA was mainly present in vascular SMCs and osteoblastic cells in calcified and ossified regions in the plaque.
In situ hybridization of BMP-2 and BMP-4 in fibrocalcific plaques showed mRNA expression in intimal vascular SMCs, mainly surrounding the calcified areas, and in osteoblasts, whereas mRNA expression was absent in medial vascular SMCs. This mRNA expression pattern was comparable to immunohistochemical localization of these proteins.
In addition, in situ hybridization of OPN and ON revealed an mRNA expression profile that resembled the protein expression profile. OPN mRNA expression was present in SMCs and in bone structures of the fibrocalcific plaque, in the osteocytes and osteoblasts. ON mRNA was highly expressed in matrix-producing SMCs and in chondrocyte-like cells. For in situ hybridization results, see Figure IV at www.atvb.ahajournals.org.
| Discussion |
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Inhibitors of Calcification (MGP, OC, and BSP)
Analysis of knockout mice has shown that both vitamin K-dependent,
-carboxyglutamic acid (Gla)containing proteins MGP and OC are inhibitors of calcification.22,23 MGP is found in bone, in the normal and atherosclerotic vessel wall,18 and in serum of patients with diabetes.14 Mice that lack MGP develop to term but die within 2 months of birth as a result of arterial calcification, which leads to blood vessel rupture.22,24 Serum OC is used as an early marker of bone turnover25 and is increased in women with aortic atherosclerosis.26 OC-deficient mice exhibit an increased bone formation23 but have normal blood vessels. MGP and OC protein are present in calcium deposits in advanced human lesions,27 which corroborates our results.
BSP is a secreted glycoprotein and contains an Arg-Gly-Asp (RGD) sequence. It is expressed in highly proliferating marrow stromal cells28 and cementoblasts and might be implicated in the preferential seeding and growth of metastatic cells in bone. Elevated serum BSP is found in patients with ankylosing spondylitis.29 However, the proposed function of BSP as a regulator of bone mineralization has not yet been confirmed in vivo.30 The potential of BSP to nucleate hydroxyapatite31 suggests that this protein may act as an activator of calcification. However, in the present study, continuous immunoreactivity of BSP during all stages of human atherosclerosis was observed, and this may suggest that BSP is also involved in the inhibition of arterial calcification.
Activators of Calcification (BMP-2, BMP-4, OPN, and ON)
Two members of the transforming growth factor-ß superfamily, BMP-2 and BMP-4, are secreted signaling molecules present in bone tissue. Individual BMPs are prominent at many sites during embryonic development and organogenesis. BMP-2 can induce ectopic bone and cartilage formation in adult vertebrates.32 Administration of recombinant BMP-2 in animals results in an enhancement of fracture repair,33 and BMP-2 is currently being evaluated in clinical studies.
BMP-4 plays an important role in the onset of human endochondral bone formation, and a reduction in BMP-4 expression is associated with a variety of bone diseases. Expression of BMP-4 can be stimulated by antiestrogens but not by estrogens or other steroid hormones.34 BMP-4 is expressed in human fetal osteoblast cells, and its mRNA level is increased during differentiation of ameloblasts and odontoblasts into teeth.35 Although BMP-2 mRNA expression was reported to be present in vascular SMCs of advanced human atherosclerotic plaques,36 we are the first to show where BMP-2 and BMP-4 proteins are localized during atherogenesis.
OPN is an acidic phosphorylated glycoprotein that binds calcium and contains an RGD motif for interaction with the integrin family of cell adhesion molecules. It can act as both a cytokine and an extracellular matrix protein.37 It is expressed by chondrocytes and is found in several tissues, such as brain and heart; in calcified and noncalcified arterial lesions38; and in mitral valves.39 In OPN mutant mice, embryogenesis occurred normally, and mice were fertile.40 The mutant mice, however, had disorganization of matrix and alteration of collagen fibrillogenesis. This phenomenon could also be active in atherosclerosis, although no vascular phenotype was reported in these mice.
ON, a bone glycoprotein also known as SPARC (secreted protein, acidic and rich in cystein) binds tightly to hydroxyapatite and collagen. ON is a protein widely expressed in different tissues, such as teeth and psammoma bodies.41 It is involved in cell matrix interaction, wound repair, angiogenesis, vascular permeability, cataract formation,42 and carcinogenesis. ON-deficient mice have decreased bone formation and decreased osteoblast and osteoclast surface and number, which leads to a decrease in bone formation and remodeling, with a negative bone balance that causes profound osteopenia43 and severe cataract formation. There are no data available regarding the vasculature of these mice. Immunoreactivity of OPN and ON in advanced human atherosclerotic plaques was described previously,27 and the localization of these proteins agrees with our results. Thus, OPN and ON may also act as positive regulators of vascular calcification.
Modulators of Osteoclastogenesis (OPG and OPGL)
OPG, a naturally occurring protein related to the tumor necrosis factor receptor family, is an inhibitor of osteoclast formation.44 OPG is present in bone marrow stromal cells, osteoblast-like cells, and osteosarcoma cells; in odontoblasts, ameloblasts, and pulp cells in teeth; in (pre-)osteoblasts and lining cells in bone; in endothelial cells; and occasionally in osteocytes. OPG-deficient mice exhibit a decrease in total bone density with a high incidence of bone fractures.45 These mice also exhibit medial calcification of the aorta and renal arteries.24 This corresponds with the results of a recently published study that showed that progression of atherosclerotic calcification is associated with increased bone loss in women during menopause.46 Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for osteoporosis. These results also suggest that OPG might play a role in the association between osteoporosis and vascular calcification. OPG also blocks pain-related behavior in mice with bone cancer, and it may provide an effective treatment against pain in human bone cancer.47 The presence of OPG in the borders of bone structures harmonizes with its function as an inhibitor of bone resorption, most likely by inhibition of osteoclastogenesis. No immunoreactivity with OPG could be demonstrated in or around calcified areas of the vessel wall, which might coincide with the arterial calcification in OPG-deficient mice.
OPGL, also known as RANKL, is a membrane-bound ligand expressed by bone marrow stromal cells and is a stimulator of osteoclastogenesis. In bone, osteoblasts/stromal cells regulate osteoclast formation by the production of cytokines like OPG and OPGL. Estrogens suppress OPGL-induced osteoclast differentiation, whereas prostaglandin E2 induces expression of OPGL.48 OPGL binds to RANK, a transmembrane receptor on hemopoietic osteoclast precursor cells. OPGL is also present in bone marrow stromal cells, osteosarcoma cells, odontoblasts, ameloblasts, and pulp cells; in tumors associated with bone lysis; and in patients with rheumatoid arthritis.49 Mice with a disrupted OPGL gene show severe osteopetrosis and defects in early differentiation of T and B lymphocytes.50 There are no data available regarding the vasculature of these mice. In the present study, OPGL was only present in the extracellular matrix surrounding the calcium mineral deposits of the plaques. This suggests that OPGL is involved in the regulation of early mineralization in atherosclerotic lesions.
In contrast to Schinke and Karsenty,24 who postulated that vascular calcification is a passive process that requires active inhibition, the major conclusion derived from our data is that atherosclerotic calcification is an active process regulated by inhibitors and activators of calcification and bone formation. According to our data, inhibitor proteins continuously prevent calcification, whereas the restricted presence of activators provides an imbalance, finally resulting in atherosclerotic calcification. Whether bone structure formation in the arterial wall is also mediated by changes in osteoclast formation remains to be elucidated.
| Acknowledgments |
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Received October 24, 2000; accepted August 31, 2001.
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Y. Yao, A. D. Watson, S. Ji, and K. I. Bostrom Heat Shock Protein 70 Enhances Vascular Bone Morphogenetic Protein-4 Signaling by Binding Matrix Gla Protein Circ. Res., September 11, 2009; 105(6): 575 - 584. [Abstract] [Full Text] [PDF] |
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M. Mizobuchi, D. Towler, and E. Slatopolsky Vascular Calcification: The Killer of Patients with Chronic Kidney Disease J. Am. Soc. Nephrol., July 1, 2009; 20(7): 1453 - 1464. [Abstract] [Full Text] [PDF] |
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S. Panizo, A. Cardus, M. Encinas, E. Parisi, P. Valcheva, S. Lopez-Ongil, B. Coll, E. Fernandez, and J. M. Valdivielso RANKL Increases Vascular Smooth Muscle Cell Calcification Through a RANK-BMP4-Dependent Pathway Circ. Res., May 8, 2009; 104(9): 1041 - 1048. [Abstract] [Full Text] [PDF] |
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S. Kwok, Y. Shin, H. Kim, H. Kim, J. Kim, S. Yoo, J. Choi, W. Kim, and C. Cho Circulating osteoprotegerin levels are elevated and correlated with antiphospholipid antibodies in patients with systemic lupus erythematosus Lupus, February 1, 2009; 18(2): 133 - 138. [Abstract] [PDF] |
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I. Kanazawa, T. Yamaguchi, M. Yamamoto, M. Yamauchi, S. Kurioka, S. Yano, and T. Sugimoto Serum Osteocalcin Level Is Associated with Glucose Metabolism and Atherosclerosis Parameters in Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 45 - 49. [Abstract] [Full Text] [PDF] |
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G. Rashid, E. Plotkin, O. Klein, J. Green, J. Bernheim, and S. Benchetrit Parathyroid hormone decreases endothelial osteoprotegerin secretion: role of protein kinase A and C Am J Physiol Renal Physiol, January 1, 2009; 296(1): F60 - F66. [Abstract] [Full Text] [PDF] |
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Y. Yao, E. S. Shao, M. Jumabay, A. Shahbazian, S. Ji, and K. I. Bostrom High-Density Lipoproteins Affect Endothelial BMP-Signaling by Modulating Expression of the Activin-Like Kinase Receptor 1 and 2 Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2266 - 2274. [Abstract] [Full Text] [PDF] |
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S. T. Choi, J. H. Kim, E.-J. Kang, S.-W. Lee, M.-C. Park, Y.-B. Park, and S.-K. Lee Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis Rheumatology, December 1, 2008; 47(12): 1775 - 1779. [Abstract] [Full Text] [PDF] |
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L. G. Arroyo, M. A. Hayes, J. DeLay, C. Rao, B. Duncan, and L. Viel Arterial Calcification in Race Horses Veterinary Pathology, September 1, 2008; 45(5): 617 - 625. [Abstract] [Full Text] [PDF] |
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A. Csiszar, N. Labinskyy, H. Jo, P. Ballabh, and Z. Ungvari Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H569 - H577. [Abstract] [Full Text] [PDF] |
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L. L. Demer and Y. Tintut Vascular Calcification: Pathobiology of a Multifaceted Disease Circulation, June 3, 2008; 117(22): 2938 - 2948. [Full Text] [PDF] |
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S. Mathew, K. S. Tustison, T. Sugatani, L. R. Chaudhary, L. Rifas, and K. A. Hruska The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1092 - 1105. [Abstract] [Full Text] [PDF] |
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Y. Yao, A. Shahbazian, and K. I. Bostrom Proline and {gamma}-Carboxylated Glutamate Residues in Matrix Gla Protein Are Critical for Binding of Bone Morphogenetic Protein-4 Circ. Res., May 9, 2008; 102(9): 1065 - 1074. [Abstract] [Full Text] [PDF] |
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T. Omland, T. Ueland, A. M. Jansson, A. Persson, T. Karlsson, C. Smith, J. Herlitz, P. Aukrust, M. Hartford, and K. Caidahl Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J. Am. Coll. Cardiol., February 12, 2008; 51(6): 627 - 633. [Abstract] [Full Text] [PDF] |
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S. Morony, Y. Tintut, Z. Zhang, R. C. Cattley, G. Van, D. Dwyer, M. Stolina, P. J. Kostenuik, and L. L. Demer Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr( / ) Mice Circulation, January 22, 2008; 117(3): 411 - 420. [Abstract] [Full Text] [PDF] |
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A. Lawrie, E. Waterman, M. Southwood, D. Evans, J. Suntharalingam, S. Francis, D. Crossman, P. Croucher, N. Morrell, and C. Newman Evidence of a Role for Osteoprotegerin in the Pathogenesis of Pulmonary Arterial Hypertension Am. J. Pathol., January 1, 2008; 172(1): 256 - 264. [Abstract] [Full Text] [PDF] |
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Y. Kanno, T. Into, C. J. Lowenstein, and K. Matsushita Nitric oxide regulates vascular calcification by interfering with TGF-{beta} signalling Cardiovasc Res, January 1, 2008; 77(1): 221 - 230. [Abstract] [Full Text] [PDF] |
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D. V. Anand, E. Lim, D. Darko, P. Bassett, D. Hopkins, D. Lipkin, R. Corder, and A. Lahiri Determinants of Progression of Coronary Artery Calcification in Type 2 Diabetes: Role of Glycemic Control and Inflammatory/Vascular Calcification Markers J. Am. Coll. Cardiol., December 4, 2007; 50(23): 2218 - 2225. [Abstract] [Full Text] [PDF] |
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D. Vega, N. M. Maalouf, and K. Sakhaee The Role of Receptor Activator of Nuclear Factor-{kappa}B (RANK)/RANK Ligand/Osteoprotegerin: Clinical Implications J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4514 - 4521. [Abstract] [Full Text] [PDF] |
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B. Nellemann, L. C. Gormsen, J. Dollerup, O. Schmitz, C. E. Mogensen, L. M. Rasmussen, and S. Nielsen Simvastatin Reduces Plasma Osteoprotegerin in Type 2 Diabetic Patients With Microalbuminuria Diabetes Care, December 1, 2007; 30(12): 3122 - 3124. [Full Text] [PDF] |
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Z. I. Ungvari Endothelium-Derived Bone Morphogenic Protein Antagonists May Counteract the Proatherogenic Vascular Effects of Bone Morphogenic Protein 4 Circulation, September 11, 2007; 116(11): 1221 - 1223. [Full Text] [PDF] |
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M. Hagen, K. Fagan, W. Steudel, M. Carr, K. Lane, D. M. Rodman, and J. West Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1473 - L1479. [Abstract] [Full Text] [PDF] |
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A. Csiszar, N. Labinskyy, K. E. Smith, A. Rivera, E. N.T.P. Bakker, H. Jo, J. Gardner, Z. Orosz, and Z. Ungvari Downregulation of Bone Morphogenetic Protein 4 Expression in Coronary Arterial Endothelial Cells: Role of Shear Stress and the cAMP/Protein Kinase A Pathway Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 776 - 782. [Abstract] [Full Text] [PDF] |
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L. J. Schurgers, H. M. H. Spronk, B. A. M. Soute, P. M. Schiffers, J. G. R. DeMey, and C. Vermeer Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats Blood, April 1, 2007; 109(7): 2823 - 2831. [Abstract] [Full Text] [PDF] |
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K. Hayashi, S. Nakamura, W. Nishida, and K. Sobue Bone Morphogenetic Protein-Induced Msx1 and Msx2 Inhibit Myocardin-Dependent Smooth Muscle Gene Transcription Mol. Cell. Biol., December 15, 2006; 26(24): 9456 - 9470. [Abstract] [Full Text] [PDF] |
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N. X. Chen, D. Duan, K. D. O'Neill, and S. M. Moe High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3435 - 3442. [Abstract] [Full Text] [PDF] |
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R. C. Johnson, J. A. Leopold, and J. Loscalzo Vascular Calcification: Pathobiological Mechanisms and Clinical Implications Circ. Res., November 10, 2006; 99(10): 1044 - 1059. [Abstract] [Full Text] [PDF] |
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M. A Allison, D. DiTomasso, M. H Criqui, R. D Langer, and C M. Wright Renal artery calcium: relationship to systemic calcified atherosclerosis Vascular Medicine, November 1, 2006; 11(4): 232 - 238. [Abstract] [PDF] |
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C. A. Davies, M. Jeziorska, A. J. Freemont, and A. L. Herrick Expression of osteonectin and matrix Gla protein in scleroderma patients with and without calcinosis Rheumatology, November 1, 2006; 45(11): 1349 - 1355. [Abstract] [Full Text] [PDF] |
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B. J. Bennett, M. Scatena, E. A. Kirk, M. Rattazzi, R. M. Varon, M. Averill, S. M. Schwartz, C. M. Giachelli, and M. E. Rosenfeld Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE-/- Mice Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 2117 - 2124. [Abstract] [Full Text] [PDF] |
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J. Y. Shin, Y. G. Shin, and C. H. Chung Elevated Serum Osteoprotegerin Levels Are Associated With Vascular Endothelial Dysfunction in Type 2 Diabetes Diabetes Care, July 1, 2006; 29(7): 1664 - 1666. [Full Text] [PDF] |
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X. Qin, M. A. Corriere, L. M. Matrisian, and R. J. Guzman Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1510 - 1516. [Abstract] [Full Text] [PDF] |
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A. H. E. M. Maas, Y. T. van der Schouw, D. Beijerinck, J. J. M. Deurenberg, W. P. T. M. Mali, and Y. van der Graaf Arterial Calcifications Seen on Mammograms: Cardiovascular Risk Factors, Pregnancy, and Lactation Radiology, July 1, 2006; 240(1): 33 - 38. [Abstract] [Full Text] [PDF] |
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S. Miriyala, M. C. Gongora Nieto, C. Mingone, D. Smith, S. Dikalov, D. G. Harrison, and H. Jo Bone Morphogenic Protein-4 Induces Hypertension in Mice: Role of Noggin, Vascular NADPH Oxidases, and Impaired Vasorelaxation Circulation, June 20, 2006; 113(24): 2818 - 2825. [Abstract] [Full Text] [PDF] |
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D. V. Anand, A. Lahiri, E. Lim, D. Hopkins, and R. Corder The Relationship Between Plasma Osteoprotegerin Levels and Coronary Artery Calcification in Uncomplicated Type 2 Diabetic Subjects J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1850 - 1857. [Abstract] [Full Text] [PDF] |
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A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF] |
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W. J. Sandberg, A. Yndestad, E. Oie, C. Smith, T. Ueland, O. Ovchinnikova, A.-K. L. Robertson, F. Muller, A. G. Semb, H. Scholz, et al. Enhanced T-Cell Expression of RANK Ligand in Acute Coronary Syndrome: Possible Role in Plaque Destabilization Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 857 - 863. [Abstract] [Full Text] [PDF] |
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M. A. Allison, P. Cheung, M. H. Criqui, R. D. Langer, and C. M. Wright Mitral and Aortic Annular Calcification Are Highly Associated With Systemic Calcified Atherosclerosis Circulation, February 14, 2006; 113(6): 861 - 866. [Abstract] [Full Text] [PDF] |
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A. Csiszar, M. Ahmad, K. E. Smith, N. Labinskyy, Q. Gao, G. Kaley, J. G. Edwards, M. S. Wolin, and Z. Ungvari Bone Morphogenetic Protein-2 Induces Proinflammatory Endothelial Phenotype Am. J. Pathol., February 1, 2006; 168(2): 629 - 638. [Abstract] [Full Text] [PDF] |
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M. Morena, N. Terrier, I. Jaussent, H. Leray-Moragues, L. Chalabi, J.-P. Rivory, F. Maurice, C. Delcourt, J.-P. Cristol, B. Canaud, et al. Plasma Osteoprotegerin Is Associated with Mortality in Hemodialysis Patients J. Am. Soc. Nephrol., January 1, 2006; 17(1): 262 - 270. [Abstract] [Full Text] [PDF] |
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M. M. McCormick, F. Rahimi, Y. V. Bobryshev, K. Gaus, H. Zreiqat, H. Cai, R. S. A. Lord, and C. L. Geczy S100A8 and S100A9 in Human Arterial Wall: IMPLICATIONS FOR ATHEROGENESIS J. Biol. Chem., December 16, 2005; 280(50): 41521 - 41529. [Abstract] [Full Text] [PDF] |
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F. Galluzzi, S. Stagi, R. Salti, S. Toni, E. Piscitelli, G. Simonini, F. Falcini, and F. Chiarelli Osteoprotegerin serum levels in children with type 1 diabetes: a potential modulating role in bone status Eur. J. Endocrinol., December 1, 2005; 153(6): 879 - 885. [Abstract] [Full Text] [PDF] |
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M. C. Bezerra, G. D. Calomeni, V. F. Caparbo, E. S. Gebrim, M. S. Rocha, and R. M. R. Pereira Low bone density and low serum levels of soluble RANK ligand are associated with severe arterial calcification in patients with Takayasu arteritis Rheumatology, December 1, 2005; 44(12): 1503 - 1506. [Abstract] [Full Text] [PDF] |
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X. Guang-da, S. Hui-ling, C. Zhi-song, and Z. Lin-shuang Changes in Plasma Concentrations of Osteoprotegerin before and after Levothyroxine Replacement Therapy in Hypothyroid Patients J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5765 - 5768. [Abstract] [Full Text] [PDF] |
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K. Schapira, E. Lutgens, A. de Fougerolles, A. Sprague, A. Roemen, H. Gardner, V. Koteliansky, M. Daemen, and S. Heeneman Genetic Deletion or Antibody Blockade of {alpha}1{beta}1 Integrin Induces a Stable Plaque Phenotype in ApoE-/- Mice Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1917 - 1924. [Abstract] [Full Text] [PDF] |
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J. Adams and J. Pepping Vitamin K in the treatment and prevention of osteoporosis and arterial calcification Am. J. Health Syst. Pharm., August 1, 2005; 62(15): 1574 - 1581. [Abstract] [Full Text] [PDF] |
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K. A. Hruska, S. Mathew, and G. Saab Bone Morphogenetic Proteins in Vascular Calcification Circ. Res., July 22, 2005; 97(2): 105 - 114. [Abstract] [Full Text] [PDF] |
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J.-K. Min, Y.-M. Kim, S. W. Kim, M.-C. Kwon, Y.-Y. Kong, I. K. Hwang, M. H. Won, J. Rho, and Y.-G. Kwon TNF-Related Activation-Induced Cytokine Enhances Leukocyte Adhesiveness: Induction of ICAM-1 and VCAM-1 via TNF Receptor-Associated Factor and Protein Kinase C-Dependent NF-{kappa}B Activation in Endothelial Cells J. Immunol., July 1, 2005; 175(1): 531 - 540. [Abstract] [Full Text] [PDF] |
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M. Rattazzi, B. J. Bennett, F. Bea, E. A. Kirk, J. L. Ricks, M. Speer, S. M. Schwartz, C. M. Giachelli, and M. E. Rosenfeld Calcification of Advanced Atherosclerotic Lesions in the Innominate Arteries of ApoE-Deficient Mice: Potential Role of Chondrocyte-Like Cells Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1420 - 1425. [Abstract] [Full Text] [PDF] |
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A. Csiszar, K. E. Smith, A. Koller, G. Kaley, J. G. Edwards, and Z. Ungvari Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells: Role of Nuclear Factor-{kappa}B Activation by Tumor Necrosis Factor-{alpha}, H2O2, and High Intravascular Pressure Circulation, May 10, 2005; 111(18): 2364 - 2372. [Abstract] [Full Text] [PDF] |
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C. A. Simmons, G. R. Grant, E. Manduchi, and P. F. Davies Spatial Heterogeneity of Endothelial Phenotypes Correlates With Side-Specific Vulnerability to Calcification in Normal Porcine Aortic Valves Circ. Res., April 15, 2005; 96(7): 792 - 799. [Abstract] [Full Text] [PDF] |
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J. W. Fischer, S. A. Steitz, P. Y. Johnson, A. Burke, F. Kolodgie, R. Virmani, C. Giachelli, and T. N. Wight Decorin Promotes Aortic Smooth Muscle Cell Calcification and Colocalizes to Calcified Regions in Human Atherosclerotic Lesions Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2391 - 2396. [Abstract] [Full Text] [PDF] |
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P. Collin-Osdoby Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin Circ. Res., November 26, 2004; 95(11): 1046 - 1057. [Abstract] [Full Text] [PDF] |
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L. J. Schurgers, H. Aebert, C. Vermeer, B. Bultmann, and J. Janzen Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood, November 15, 2004; 104(10): 3231 - 3232. [Abstract] [Full Text] [PDF] |
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S. M. Moe and N. X. Chen Pathophysiology of Vascular Calcification in Chronic Kidney Disease Circ. Res., September 17, 2004; 95(6): 560 - 567. [Abstract] [Full Text] [PDF] |
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T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF] |
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M. Soufi, M. Schoppet, A. M. Sattler, M. Herzum, B. Maisch, L. C. Hofbauer, and J. R. Schaefer Osteoprotegerin Gene Polymorphisms in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3764 - 3768. [Abstract] [Full Text] [PDF] |
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M. Schoppet, N. Al-Fakhri, F. E. Franke, N. Katz, P. J. Barth, B. Maisch, K. T. Preissner, and L. C. Hofbauer Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-{kappa}B Ligand in Monckeberg's Sclerosis and Atherosclerosis J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4104 - 4112. [Abstract] [Full Text] [PDF] |
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M. Abedin, Y. Tintut, and L. L. Demer Vascular Calcification: Mechanisms and Clinical Ramifications Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1161 - 1170. [Abstract] [Full Text] [PDF] |
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S. Kiechl, G. Schett, G. Wenning, K. Redlich, M. Oberhollenzer, A. Mayr, P. Santer, J. Smolen, W. Poewe, and J. Willeit Osteoprotegerin Is a Risk Factor for Progressive Atherosclerosis and Cardiovascular Disease Circulation, May 11, 2004; 109(18): 2175 - 2180. [Abstract] [Full Text] [PDF] |
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R. Vattikuti and D. A. Towler Osteogenic regulation of vascular calcification: an early perspective Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E686 - E696. [Abstract] [Full Text] [PDF] |
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D. J. Grainger Transforming Growth Factor {beta} and Atherosclerosis: So Far, So Good for the Protective Cytokine Hypothesis Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 399 - 404. [Abstract] [Full Text] |
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T. M. Doherty, L. A. Fitzpatrick, A. Shaheen, T. B. Rajavashisth, and R. C. Detrano Genetic Determinants of Arterial Calcification Associated With Atherosclerosis Mayo Clin. Proc., February 1, 2004; 79(2): 197 - 210. [Abstract] [PDF] |
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M. Schoppet, J. R. Schaefer, L. C. Hofbauer, S. Jono, K. Mori, Y. Nishizawa, A. Shioi, T. Miki, Y. Ikari, and K. Hara Low Serum Levels of Soluble RANK Ligand Are Associated With the Presence of Coronary Artery Disease in Men * Response Circulation, March 25, 2003; 107 (11): e76 - e76. [Full Text] [PDF] |
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M. Schoppet, A. M. Sattler, J. R. Schaefer, M. Herzum, B. Maisch, and L. C. Hofbauer Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1024 - 1028. [Abstract] [Full Text] [PDF] |
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K. L. Tyson, J. L. Reynolds, R. McNair, Q. Zhang, P. L. Weissberg, and C. M. Shanahan Osteo/Chondrocytic Transcription Factors and Their Target Genes Exhibit Distinct Patterns of Expression in Human Arterial Calcification Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 489 - 494. [Abstract] [Full Text] [PDF] |
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G. J. Adams, D. M. Simoni, C. B. Bordelon Jr, G. W. Vick III, K. T. Kimball, W. Insull Jr, and J. D. Morrisett Bilateral Symmetry of Human Carotid Artery Atherosclerosis Stroke, November 1, 2002; 33(11): 2575 - 2580. [Abstract] [Full Text] [PDF] |
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M. Y. Speer, M. D. McKee, R. E. Guldberg, L. Liaw, H.-Y. Yang, E. Tung, G. Karsenty, and C. M. Giachelli Inactivation of the Osteopontin Gene Enhances Vascular Calcification of Matrix Gla Protein-deficient Mice: Evidence for Osteopontin as an Inducible Inhibitor of Vascular Calcification In Vivo J. Exp. Med., October 21, 2002; 196(8): 1047 - 1055. [Abstract] [Full Text] [PDF] |
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S. Jono, Y. Ikari, A. Shioi, K. Mori, T. Miki, K. Hara, and Y. Nishizawa Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease Circulation, September 3, 2002; 106(10): 1192 - 1194. [Abstract] [Full Text] [PDF] |
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