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      Nucleotide Catabolism on the Surface of Aortic Valve Xenografts; Effects of Different Decellularization Strategies

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          Abstract

          Extracellular nucleotide metabolism controls thrombosis and inflammation and may affect degeneration and calcification of aortic valve prostheses. We evaluated the effect of different decellularization strategies on enzyme activities involved in extracellular nucleotide metabolism. Porcine valves were tested intact or decellularized either by detergent treatment or hypotonic lysis and nuclease digestion. The rates of ATP hydrolysis, AMP hydrolysis, and adenosine deamination were estimated by incubation of aorta or valve leaflet sections with substrates followed by HPLC analysis. We demonstrated relatively high activities of ecto-enzymes on porcine valve as compared to the aortic wall. Hypotonic lysis/nuclease digestion preserved >80 % of ATP and AMP hydrolytic activity but reduced adenosine deamination to <10 %. Detergent decellularization completely removed (<5 %) all these activities. These results demonstrate high intensity of extracellular nucleotide metabolism on valve surface and indicate that various valve decellularization techniques differently affect ecto-enzyme activities that could be important in the development of improved valve prostheses.

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          Most cited references43

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          Decellularization of tissues and organs.

          Decellularized tissues and organs have been successfully used in a variety of tissue engineering/regenerative medicine applications, and the decellularization methods used vary as widely as the tissues and organs of interest. The efficiency of cell removal from a tissue is dependent on the origin of the tissue and the specific physical, chemical, and enzymatic methods that are used. Each of these treatments affect the biochemical composition, tissue ultrastructure, and mechanical behavior of the remaining extracellular matrix (ECM) scaffold, which in turn, affect the host response to the material. Herein, the most commonly used decellularization methods are described, and consideration give to the effects of these methods upon the biologic scaffold material.
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            Calcification of tissue heart valve substitutes: progress toward understanding and prevention.

            Calcification plays a major role in the failure of bioprosthetic and other tissue heart valve substitutes. Tissue valve calcification is initiated primarily within residual cells that have been devitalized, usually by glutaraldehyde pretreatment. The mechanism involves reaction of calcium-containing extracellular fluid with membrane-associated phosphorus to yield calcium phosphate mineral deposits. Calcification is accelerated by young recipient age, valve factors such as glutaraldehyde fixation, and increased mechanical stress. Recent studies have suggested that pathologic calcification is regulated by inductive and inhibitory factors, similar to the physiologic mineralization of bone. The most promising preventive strategies have included binding of calcification inhibitors to glutaraldehyde fixed tissue, removal or modification of calcifiable components, modification of glutaraldehyde fixation, and use of tissue cross linking agents other than glutaraldehyde. This review summarizes current concepts in the pathophysiology of tissue valve calcification, including emerging concepts of endogenous regulation, progress toward prevention of calcification, and issues related to calcification of the aortic wall of stentless bioprosthetic valves.
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              NT5E mutations and arterial calcifications.

              Arterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear. We performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed. We identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662C→A, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073G→A, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662C→A and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification. We identified mutations in NT5E in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification. (Funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.).
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                Author and article information

                Contributors
                + 48 58 349 14 64 , rt.smolenski@gmail.com
                Journal
                J Cardiovasc Transl Res
                J Cardiovasc Transl Res
                Journal of Cardiovascular Translational Research
                Springer US (New York )
                1937-5387
                1937-5395
                1 February 2016
                1 February 2016
                2016
                : 9
                : 119-126
                Affiliations
                [ ]Department of Biochemistry, Medical University of Gdansk, Gdańsk, Poland
                [ ]Heart Science Centre, Imperial College London, London, UK
                [ ]University of Arizona, Tucson, AZ USA
                [ ]CryoLife, Inc, Kennesaw, GA USA
                [ ]University Milano-Bicocca, Milan, Italy
                Author notes

                Associate Editor Daniel P. Judge oversaw the review of this article

                Article
                9672
                10.1007/s12265-016-9672-6
                4830859
                26832118
                a1eaec57-a4ee-4312-8669-05312bdf5d9b
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 28 October 2015
                : 4 January 2016
                Funding
                Funded by: Foundation for Polish Science
                Award ID: TEAM/2011-8/7
                Award Recipient :
                Funded by: National Science Centre of Poland
                Award ID: 2011/01/B/NZ4/03719
                Award Recipient :
                Funded by: Italian Ministry of Education, University and Research by the Fund for Investments on Basic Research
                Award ID: RBAP06LAHL
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer Science+Business Media New York 2016

                Cardiovascular Medicine
                (max 10) heart valves,xenografts,nucleotide metabolism,atp,adenosine,valve prostheses

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