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      Periostin Expression is Altered in Aortic Valves in Smad6 Mutant Mice

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          Abstract

          Smad6 is known to predominantly inhibit BMP signaling by negatively regulating the BMP signaling process. Therefore, Smad6 mutation potentially provides an important genetic model for investigating the role of BMP signaling in vivo. Periostin is a 90-kDA secreted extracellular matrix (ECM) protein and implicated in cardiac valve progenitor cell differentiation, maturation and adult aortic valve calcification in mice. We have previously reported periostin expression patterns during AV valve development in mice. Because periostin can play critical roles in aortic valve interstitial cell differentiation and can be correlated with adult valve disease pathogenesis, in the present study we specifically focused on periostin expression during outflow tract (OT) development and its expression within the adult mouse valves. We previously reported that periostin expression in valve progenitor cells was altered by exogenously adding BMP-2 in culture. In this study, we investigated whether expression of periostin and other valvulogenic ECM proteins was altered in Smad6-mutant newborn mice in vivo. Periostin protein was localized within OT during embryonic development in mice. At embryonic day (ED) 13.5, robust periostin expression was detected within the developing pulmonary trunk and developing pulmonary and aortic valves. Periostin expression remained intense in pulmonary and aortic valves up to the adult stage. Our immunohistochemical and immunointensity analyses revealed that periostin expression was significantly reduced in the aortic valves in Smad6−/− neonatal hearts. Versican expression was also significantly reduced in Smad6−/− aortic valves, whereas, hyaluronan deposition was not significantly altered in the Smad6−/− neonatal valves. Expression of periostin and versican was less prominently affected in AV valves compared to the aortic valves, suggesting that a cell lineage/origin-dependent response to regulatory molecules may play a critical role in valve interstitial cell development and ECM protein expression.

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          Most cited references42

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          The incidence of congenital heart disease.

          This study was designed to determine the reasons for the variability of the incidence of congenital heart disease (CHD), estimate its true value and provide data about the incidence of specific major forms of CHD. The incidence of CHD in different studies varies from about 4/1,000 to 50/1,000 live births. The relative frequency of different major forms of CHD also differs greatly from study to study. In addition, another 20/1,000 live births have bicuspid aortic valves, isolated anomalous lobar pulmonary veins or a silent patent ductus arteriosus. The incidences reported in 62 studies published after 1955 were examined. Attention was paid to the ways in which the studies were conducted, with special reference to the increased use of echocardiography in the neonatal nursery. The total incidence of CHD was related to the relative frequency of ventricular septal defects (VSDs), the most common type of CHD. The incidences of individual major forms of CHD were determined from 44 studies. The incidence of CHD depends primarily on the number of small VSDs included in the series, and this number in turn depends upon how early the diagnosis is made. If major forms of CHD are stratified into trivial, moderate and severe categories, the variation in incidence depends mainly on the number of trivial lesions included. The incidence of moderate and severe forms of CHD is about 6/1,000 live births (19/1,000 live births if the potentially serious bicuspid aortic valve is included), and of all forms increases to 75/1,000 live births if tiny muscular VSDs present at birth and other trivial lesions are included. Given the causes of variation, there is no evidence for differences in incidence in different countries or times.
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            Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.

            The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.
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              Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.

              We identified hyaluronan synthase-2 (Has2) as a likely source of hyaluronan (HA) during embryonic development, and we used gene targeting to study its function in vivo. Has2(-/-) embryos lack HA, exhibit severe cardiac and vascular abnormalities, and die during midgestation (E9.5-10). Heart explants from Has2(-/-) embryos lack the characteristic transformation of cardiac endothelial cells into mesenchyme, an essential developmental event that depends on receptor-mediated intracellular signaling. This defect is reproduced by expression of a dominant-negative Ras in wild-type heart explants, and is reversed in Has2(-/-) explants by gene rescue, by administering exogenous HA, or by expressing activated Ras. Conversely, transformation in Has2(-/-) explants mediated by exogenous HA is inhibited by dominant-negative Ras. Collectively, our results demonstrate the importance of HA in mammalian embryogenesis and the pivotal role of Has2 during mammalian development. They also reveal a previously unrecognized pathway for cell migration and invasion that is HA-dependent and involves Ras activation.
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                Author and article information

                Journal
                101606488
                41240
                J Neonatal Biol
                J Neonatal Biol
                Journal of neonatal biology
                2167-0897
                26 April 2013
                21 January 2012
                07 November 2014
                : 1
                : 4692
                Affiliations
                Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Medical University of South Carolina, USA
                Author notes
                [* ] Corresponding author: Yukiko Sugi, PhD, Associate Professor, Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Medical University of South Carolina, BSB Rm. 635, 171 Ashley Avenue, Charleston SC 29425 USA, Tel: 843 792 6501; Fax: 843 792 0664; sugiy@ 123456musc.edu
                Article
                NIHMS439453
                10.4172/2167-0897.1000101
                4224111
                04487e16-d5f0-43e5-9235-d84b8b8e148e
                Copyright: © 2012 Sugi Y et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Categories
                Article

                periostin,versican,smad6,hyaluronan,heart valve,outflow tract,endocardial cushion

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