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      The Functional Role of C-Reactive Protein in Aortic Wall Calcification


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          As an ongoing effort to elucidate the mechanisms involved in bioprosthetic heart valve (BHV) calcification, the role of C-reactive protein (CRP) in the tissue calcification process was investigated. The profile of calcium-associated proteins (CAP) on glutaraldehyde-preserved (0.6%) porcine aortic wall, which were subcutaneously implanted in rats for up to 8 weeks, showed a temporal appearance pattern. The total extracted amount of proteins from the control tissues implanted for 8 weeks was significantly greater than that from ethanol-treated tissues (1.78 ± 0.2 vs. 1.27 ± 0.18 µg/mg), indicating that the binding affinity of CAP for BHV pretreated with an anticalcification agent was significantly decreased (p < 0.05). The dye Stains-All method showed that the dark-blue colored bands, representing high calcium binding and phosphorylated proteins, were stained from the extract of the control BHV at the molecular weight varying from 4 to 250 kDa, but rarely seen in the extract of BHV pretreated with ethanol. One of those proteins was exclusively immunoreactive with CRP antibody, while there was no immunoreaction in less calcified tissues. When aortic wall was exposed to an excess amount of CRP in an in vitro simulating model, the calcification rate of aortic wall increased as the concentration of CRP increased. The results of this work clearly revealed that CRP has indirect vascular effects, leading to an increased rate of aortic wall calcification.

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          Most cited references 26

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          Osteonectin, a bone-specific protein linking mineral to collagen.

          Osteonectin is a 32,000 dalton bone-specific protein that binds selectively to both hydroxyapatite and collagen. When osteonectin is bound to insolubilized type I collagen, the resultant complex binds synthetic apatite crystals and free calcium ions. The osteonectin-collagen complexes also nucleate mineral phase deposition from metastable balanced salt solutions, Antibodies to osteonectin cross-react with bone and, to a lesser extent, dentin, but not with other tissues. The protein is localized to mineralized bone trabeculae and occurs at higher levels in the matrix than in the cells of bone. These studies suggest that osteonectin is a tissue-specific protein, linking the bone mineral and collagen phases, perhaps initiating active mineralization in normal skeletal tissue.
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            Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease.

            Plasma and whole-body turnover studies of human C-reactive protein (CRP), isolated from a single normal healthy donor and labeled with 125I, were undertaken in 8 healthy control subjects and 35 hospitalized patients including cases of rheumatoid arthritis, systemic lupus erythematosus, infections, and neoplasia. Plasma clearance of 125I-CRP closely approximated to a monoexponential function and was similar in the control and all patient groups. There was no evidence for accelerated clearance or catabolism of CRP in any of the diseases studied. The 19-h half-life was more rapid than that of most human plasma proteins studied previously, and the fractional catabolic rate was independent of the plasma CRP concentration. The synthesis rate of CRP is thus the only significant determinant of its plasma level, confirming the validity of serum CRP measurement as an objective index of disease activity in disorders associated with an acute-phase response. Approximately 90% of injected radioactivity was recovered in the urine after 7 d, and scintigraphic imaging studies with 123I-labeled CRP in 10 patients with different focal pathology showed no significant localization of tracer. The functions of CRP are thus likely to be effected predominantly in the fluid phase rather than by major deposition at sites of tissue damage or inflammation.
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              High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

              Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability.

                Author and article information

                S. Karger AG
                August 2005
                24 August 2005
                : 104
                : 2
                : 57-64
                Department of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Mo., USA
                86686 Cardiology 2005;104:57–64
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 51, Pages: 8
                General Cardiology – Basic Science


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