{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:52:12Z","timestamp":1787003532103,"version":"build-2736575974"},"reference-count":92,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL007260"],"award-info":[{"award-number":["HL007260"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM127200"],"award-info":[{"award-number":["P30GM127200"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["S10OD010731"],"award-info":[{"award-number":["S10OD010731"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"name":"South Carolina Centers of Economic Excellence SmartState Program"},{"name":"National Cancer Institute","award":["U01CA242096"],"award-info":[{"award-number":["U01CA242096"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["16GRNT31380005"],"award-info":[{"award-number":["16GRNT31380005"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007316","name":"Division of Cancer Prevention, National Cancer Institute","doi-asserted-by":"publisher","award":["R21CA240148"],"award-info":[{"award-number":["R21CA240148"]}],"id":[{"id":"10.13039\/100007316","id-type":"DOI","asserted-by":"publisher"}]},{"name":"South Carolina COBRE in Oxidants, Redox Balance and Stress Signaling","award":["GM 103542"],"award-info":[{"award-number":["GM 103542"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Congenital aortic valve stenosis (CAVS) affects up to 10% of the world population without medical therapies to treat the disease. New molecular targets are continually being sought that can halt CAVS progression. Collagen deregulation is a hallmark of CAVS yet remains mostly undefined. Here, histological studies were paired with high resolution accurate mass (HRAM) collagen-targeting proteomics to investigate collagen fiber production with collagen regulation associated with human AV development and pediatric end-stage CAVS (pCAVS). Histological studies identified collagen fiber realignment and unique regions of high-density collagen in pCAVS. Proteomic analysis reported specific collagen peptides are modified by hydroxylated prolines (HYP), a post-translational modification critical to stabilizing the collagen triple helix. Quantitative data analysis reported significant regulation of collagen HYP sites across patient categories. Non-collagen type ECM proteins identified (26 of the\u00a044 total proteins) have direct interactions in collagen synthesis, regulation, or modification. Network analysis identified BAMBI (BMP and Activin Membrane Bound Inhibitor) as a potential upstream regulator of the collagen interactome. This is the first study to detail the collagen types and HYP modifications associated with human AV development and pCAVS. We anticipate that this study will inform new therapeutic avenues that inhibit valvular degradation in pCAVS and engineered options for valve replacement.<\/jats:p>","DOI":"10.1038\/s41598-021-89164-w","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T06:12:23Z","timestamp":1620367943000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Collagen fiber regulation in human pediatric aortic valve development and disease"],"prefix":"10.1038","volume":"11","author":[{"given":"Cassandra L.","family":"Clift","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Ru","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bichell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather C.","family":"Jensen Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Bethard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Norris-Caneda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Comte-Walters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Ball","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Hollingsworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand S.","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R.","family":"Drake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggi M.","family":"Angel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"key":"89164_CR1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.ahj.2003.05.003","volume":"147","author":"JIE Hoffman","year":"2004","unstructured":"Hoffman, J. I. E., Kaplan, S. & Liberthson, R. R. Prevalence of congenital heart disease. Am. Heart J. 147, 425\u2013439. https:\/\/doi.org\/10.1016\/j.ahj.2003.05.003 (2004).","journal-title":"Am. Heart J."},{"key":"89164_CR2","unstructured":"Kirklin JW, Barratt-Boyes BG. Congenital aortic stenosis. In Kirklin JW, Barratt-Boyes BG, eds. Cardiac Surgery. 2nd ed. New York: Churchill\nLivingstone, 1195\u20131237 (1993)"},{"key":"89164_CR3","first-page":"91","volume":"97","author":"JL d'Arcy","year":"2010","unstructured":"d\u2019Arcy, J. L., Prendergast, B. D., Chambers, J. B., Ray, S. G. & Bridgewater, B. Valvular heart disease: the next cardiac epidemic. BMJ 97, 91\u201393 (2010).","journal-title":"BMJ"},{"key":"89164_CR4","doi-asserted-by":"publisher","first-page":"2858","DOI":"10.1016\/j.jacc.2016.04.021","volume":"67","author":"MTA Sharabiani","year":"2016","unstructured":"Sharabiani, M. T. A. et al. Aortic valve replacement and the ross operation in children and young adults. J. Am. Coll. Cardiol. 67, 2858\u20132870. https:\/\/doi.org\/10.1016\/j.jacc.2016.04.021 (2016).","journal-title":"J. Am. Coll. Cardiol."},{"key":"89164_CR5","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1161\/01.RES.0000224114.65109.4e","volume":"98","author":"RB Hinton","year":"2006","unstructured":"Hinton, R. B. et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ. Res. 98, 1431\u20131438. https:\/\/doi.org\/10.1161\/01.RES.0000224114.65109.4e (2006).","journal-title":"Circ. Res."},{"key":"89164_CR6","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1161\/CIRCRESAHA.108.177238","volume":"103","author":"AK Levay","year":"2008","unstructured":"Levay, A. K. et al. Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo. Circ. Res. 103, 948\u2013956. https:\/\/doi.org\/10.1161\/CIRCRESAHA.108.177238 (2008).","journal-title":"Circ. Res."},{"key":"89164_CR7","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1161\/CIRCULATIONAHA.105.591768","volume":"113","author":"E Aikawa","year":"2006","unstructured":"Aikawa, E. et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113, 1344\u20131352. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.105.591768 (2006).","journal-title":"Circulation"},{"key":"89164_CR8","doi-asserted-by":"publisher","first-page":"20121004","DOI":"10.1098\/rsif.2012.1004","volume":"10","author":"A Tsamis","year":"2013","unstructured":"Tsamis, A., Krawiec, J. T. & Vorp, D. A. Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review. J. R. Soc. Interface 10, 20121004\u201320121004. https:\/\/doi.org\/10.1098\/rsif.2012.1004 (2013).","journal-title":"J. R. Soc. Interface"},{"key":"89164_CR9","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1089\/ten.TEA.2012.0316","volume":"19","author":"KP Hanson","year":"2013","unstructured":"Hanson, K. P. et al. Spatial and temporal analysis of extracellular matrix proteins in the developing murine heart: a blueprint for regeneration. Tissue Eng. Part A 19, 1132\u20131143. https:\/\/doi.org\/10.1089\/ten.TEA.2012.0316 (2013).","journal-title":"Tissue Eng. Part A"},{"key":"89164_CR10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev-physiol-012110-142145","volume":"73","author":"RB Hinton","year":"2011","unstructured":"Hinton, R. B. & Yutzey, K. E. Heart valve structure and function in development and disease. Ann. Rev. Phys. 73, 29\u201346 (2011) (PMCID: PMC4209403).","journal-title":"Ann. Rev. Phys."},{"key":"89164_CR11","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1016\/j.athoracsur.2008.12.049","volume":"87","author":"EM Joyce","year":"2009","unstructured":"Joyce, E. M., Liao, J., Schoen, F. J., Mayer, J. E. & Sacks, M. S. Functional collagen fiber architecture of the pulmonary heart valve cusp. Ann. Thorac. Surg. 87, 1240\u20131249 (2009).","journal-title":"Ann. Thorac. Surg."},{"key":"89164_CR12","doi-asserted-by":"publisher","first-page":"1864","DOI":"10.1161\/CIRCULATIONAHA.108.805911","volume":"118","author":"FJ Schoen","year":"2008","unstructured":"Schoen, F. J. Evolving concepts of cardiac valve dynamics: the continuum of development, functional structure, pathobiology, and tissue engineering. Circulation 118, 1864\u20131880 (2008) (PMID: 18955677).","journal-title":"Circulation"},{"key":"89164_CR13","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.actbio.2015.10.044","volume":"29","author":"PJA Oomen","year":"2016","unstructured":"Oomen, P. J. A. et al. Age-dependent changes of stress and strain in the human heart valve and their relation with collagen remodeling. Acta Biomater. 29, 161\u2013169 (2016).","journal-title":"Acta Biomater."},{"key":"89164_CR14","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1002\/dvdy.21719","volume":"237","author":"JD Peacock","year":"2008","unstructured":"Peacock, J. D., Lu, Y., Koch, M., Kadler, K. E. & Lincoln, J. Temporal and spatial expression of collagens during murine atrioventricular heart valve development and maintenance. Dev. Dyn. 237, 3051\u20133058 (2008).","journal-title":"Dev. Dyn."},{"key":"89164_CR15","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/bdra.20810","volume":"91","author":"M Lockhart","year":"2011","unstructured":"Lockhart, M., Wirrig, E., Phelps, A. & Wessels, A. Extracellular matrix and heart development. Birth Defects Res. A 91, 535\u2013550 (2011).","journal-title":"Birth Defects Res. A"},{"key":"89164_CR16","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.yjmcc.2010.12.005","volume":"50","author":"EE Wirrig","year":"2011","unstructured":"Wirrig, E. E., Hinton, R. B. & Yutzey, K. E. Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves. J. Mol. Cell. Cardiol. 50, 561\u2013569 (2011) (PMID: 21163264, PMCID: PMC23035730).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"89164_CR17","doi-asserted-by":"publisher","first-page":"e0163858","DOI":"10.1371\/journal.pone.0163858","volume":"11","author":"HN Hutson","year":"2016","unstructured":"Hutson, H. N. et al. Calcific aortic valve disease is associated with layer-specific alterations in collagen architecture. PLoS ONE 11, e0163858 (2016).","journal-title":"PLoS ONE"},{"key":"89164_CR18","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.atherosclerosis.2005.11.034","volume":"189","author":"HA Eriksen","year":"2006","unstructured":"Eriksen, H. A. et al. Type I and type III collagen synthesis and composition in the valve matrix in aortic valve stenosis. Atherosclerosis 189, 91\u201398 (2006).","journal-title":"Atherosclerosis"},{"key":"89164_CR19","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s10554-017-1195-y","volume":"34","author":"T Podlesnikar","year":"2018","unstructured":"Podlesnikar, T., Delgado, V. & Bax, J. J. Cardiovascular magnetic resonance imaging to assess myocardial fibrosis in valvular heart disease. Int. J. Cardiovasc. Imag. 34, 97\u2013112 (2018).","journal-title":"Int. J. Cardiovasc. Imag."},{"key":"89164_CR20","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/978-3-319-97421-7_2","volume-title":"Cardiac Extracellular Matrix","author":"MA Pinkert","year":"2018","unstructured":"Pinkert, M. A., Hortensius, R. A., Ogle, B. M. & Eliceiri, K. W. Cardiac Extracellular Matrix 21\u201344 (Springer, 2018)."},{"key":"89164_CR21","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1021\/acs.jproteome.7b00713","volume":"17","author":"PM Angel","year":"2018","unstructured":"Angel, P. M. et al. Mapping extracellular matrix proteins in formalin-fixed, paraffin-embedded tissues by MALDI imaging mass spectrometry. J. Proteome Res. 17, 635\u2013646 (2018) (PMID: 29161047).","journal-title":"J. Proteome Res."},{"key":"89164_CR22","doi-asserted-by":"publisher","first-page":"1700152","DOI":"10.1002\/prca.201700152","volume":"13","author":"PM Angel","year":"2019","unstructured":"Angel, P. M. et al. Extracellular matrix imaging of breast tissue pathologies by MALDI imaging mass spectrometry. Proteomics Clin. Appl. 13, 1700152 (2019).","journal-title":"Proteomics Clin. Appl."},{"key":"89164_CR23","doi-asserted-by":"publisher","first-page":"e4450","DOI":"10.1002\/jms.4450","volume":"55","author":"PM Angel","year":"2019","unstructured":"Angel, P. M. et al. Extracellular matrix alterations in low grade lung adenocarcinoma compared to normal lung tissue by imaging mass spectrometry. J. Mass Spectrom. 55, e4450 (2019).","journal-title":"J. Mass Spectrom."},{"key":"89164_CR24","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1002\/pros.24031","volume":"80","author":"PM Angel","year":"2020","unstructured":"Angel, P. M. et al. Zonal regulation of collagen types and post-translational modifications in prostatic benign and cancer tissues by imaging mass spectrometry. Prostate 80, 1071\u20131086 (2020).","journal-title":"Prostate"},{"key":"89164_CR25","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.7b00713","author":"PM Angel","year":"2018","unstructured":"Angel, P. M. et al. Mapping extracellular matrix proteins in formalin-fixed, paraffin-embedded tissues by MALDI imaging mass spectrometry. J. Proteome Res. https:\/\/doi.org\/10.1021\/acs.jproteome.7b00713 (2018).","journal-title":"J. Proteome Res."},{"key":"89164_CR26","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.yjmcc.2010.12.005","volume":"50","author":"EE Wirrig","year":"2012","unstructured":"Wirrig, E. E., Hinton, R. B. & Yutzey, K. E. Differential expression of cartilage and bone-realted proteins in pediatric and adult diseased aortic valves. J. Mol. Cell. Cardiol. 50, 561\u2013569. https:\/\/doi.org\/10.1016\/j.yjmcc.2010.12.005 (2012).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"89164_CR27","first-page":"204","volume":"38","author":"WG Herovici","year":"1963","unstructured":"Herovici, W. G. A polychrome stain for differentiating precollagen from collagen. Stain Technol. 38, 204\u2013206 (1963).","journal-title":"Stain Technol."},{"key":"89164_CR28","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","volume":"78","author":"MD Shoulders","year":"2009","unstructured":"Shoulders, M. D. & Raines, R. T. Collagen structure and stability. Annu. Rev. Biochem. 78, 929\u2013958 (2009) (PMID: 19344236).","journal-title":"Annu. Rev. Biochem."},{"key":"89164_CR29","doi-asserted-by":"publisher","first-page":"jcs203950","DOI":"10.1242\/jcs.203950","volume":"131","author":"AL Fidler","year":"2018","unstructured":"Fidler, A. L., Boudko, S. P., Rokas, A. & Hudson, B. G. The triple helix of collagens\u2013an ancient protein structure that enabled animal multicellularity and tissue evolution. J. Cell Sci. 131, jcs203950 (2018) (PMCID: PMC5963836).","journal-title":"J. Cell Sci."},{"key":"89164_CR30","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1042\/EBC20180070","volume":"63","author":"RW Farndale","year":"2019","unstructured":"Farndale, R. W. Collagen-binding proteins: insights from the collagen toolkits. Essays Biochem. 63, 337\u2013348. https:\/\/doi.org\/10.1042\/EBC20180070 (2019).","journal-title":"Essays Biochem."},{"key":"89164_CR31","doi-asserted-by":"publisher","first-page":"7645","DOI":"10.1074\/jbc.RA118.002200","volume":"293","author":"KH Sipila","year":"2018","unstructured":"Sipila, K. H. et al. Proline hydroxylation in collagen supports integrin binding by two distinct mechanisms. J. Biol. Chem 293, 7645\u20137658 (2018).","journal-title":"J. Biol. Chem"},{"key":"89164_CR32","doi-asserted-by":"publisher","first-page":"e0168130","DOI":"10.1371\/journal.pone.0168130","volume":"11","author":"G-C Carolina","year":"2016","unstructured":"Carolina, G.-C. et al. New altered non-fibrillar collagens in human dilated cardiomyopathy: role in the remodeling process. PLoS ONE 11, e0168130 (2016).","journal-title":"PLoS ONE"},{"key":"89164_CR33","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1089\/dna.1994.13.571","volume":"13","author":"J Skonier","year":"1994","unstructured":"Skonier, J. et al. \u03b2ig-h3: a transforming growth factor-\u03b2-responsive gene encoding a secreted protein that inhibits cell attachment in vitro and suppresses the growth of CHO cells in nude mice. DNA Cell Biol. 13, 571\u2013584 (1994).","journal-title":"DNA Cell Biol."},{"key":"89164_CR34","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/ki.1992.81","volume":"41","author":"AB Roberts","year":"1992","unstructured":"Roberts, A. B., McCune, B. K. & Sporn, M. B. TGF-beta: regulation of extracllular matrix. Kidney Int. 41, 557\u2013559 (1992).","journal-title":"Kidney Int."},{"key":"89164_CR35","first-page":"1","volume":"9","author":"N Kuroda","year":"2019","unstructured":"Kuroda, N. et al. Infiltrating CCR2+ monocytes and their progenies, fibrocytes, contribute to colon fibrosis by inhibiting collagen degradation through the production of TIMP-1. Nat. Sci. Rep. 9, 1\u201317 (2019).","journal-title":"Nat. Sci. Rep."},{"key":"89164_CR36","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1002\/emmm.201100161","volume":"3","author":"M Ling","year":"2011","unstructured":"Ling, M. & Luster, A. Novel approach to inhibiting chemokine function. EMBO Mol. Med. 3, 510\u2013512. https:\/\/doi.org\/10.1002\/emmm.201100161 (2011).","journal-title":"EMBO Mol. Med."},{"key":"89164_CR37","doi-asserted-by":"publisher","first-page":"33053","DOI":"10.1074\/jbc.M804039200","volume":"283","author":"Z Lin","year":"2008","unstructured":"Lin, Z. et al. The pseudoreceptor BMP and activin membrane-bound inhibitor positively modulates Wnt\/\u03b2-catenin signaling. J. Biol. Chem. 283, 33053\u201333058 (2008).","journal-title":"J. Biol. Chem."},{"key":"89164_CR38","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1038\/46794","volume":"401","author":"D Onichtchouk","year":"1999","unstructured":"Onichtchouk, D. et al. Silencing of TGF-\u03b2 signalling by the pseudoreceptor BAMBI. Nature 401, 480\u2013485 (1999).","journal-title":"Nature"},{"key":"89164_CR39","doi-asserted-by":"publisher","first-page":"30097","DOI":"10.1074\/jbc.M109.049304","volume":"284","author":"X Yan","year":"2009","unstructured":"Yan, X. et al. Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-\u03b2 signaling. J. Biol. Chem. 284, 30097\u201330104 (2009).","journal-title":"J. Biol. Chem."},{"key":"89164_CR40","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1016\/j.bbadis.2012.11.007","volume":"323\u2013335","author":"AV Villar","year":"1832","unstructured":"Villar, A. V. et al. BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-\u03b2 signaling. Biochim. Biophys. Acta Mol. Basis Dis. 323\u2013335, 2013. https:\/\/doi.org\/10.1016\/j.bbadis.2012.11.007 (1832).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"89164_CR41","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703","author":"A Kr\u00e4 Mer","year":"2014","unstructured":"Kr\u00e4 Mer, A., Green, J., Pollard, J. & Tugendreich, S. Systems biology causal analysis approaches in ingenuity pathway analysis. BMC Genom. https:\/\/doi.org\/10.1093\/bioinformatics\/btt703 (2014).","journal-title":"BMC Genom."},{"key":"89164_CR42","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1161\/ATVBAHA.113.302071","volume":"34","author":"EE Wirrig","year":"2014","unstructured":"Wirrig, E. E. & Yutzey, K. E. Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler. Thromb. Vasc. Biol. 34, 737\u2013741 (2014).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"89164_CR43","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3389\/fcvm.2018.00030","volume":"5","author":"E Nordquist","year":"2018","unstructured":"Nordquist, E., LaHaye, S., Nagel, C. & Lincoln, J. Postnatal and adult aortic heart valves have distinctive transcriptional profiles associated with valve tissue growth and maintenance respectively. Front. Cardiovasc. Med. 5, 30 (2018) (PMCID: PMC5928323).","journal-title":"Front. Cardiovasc. Med."},{"key":"89164_CR44","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1253\/circj.CJ-14-0510","volume":"78","author":"J Lincoln","year":"2014","unstructured":"Lincoln, J. & Garg, V. Etiology of Valvular Heart Disease. Circ. J. 78, 1801\u20131807 (2014) (PMID: 24998280).","journal-title":"Circ. J."},{"key":"89164_CR45","doi-asserted-by":"publisher","unstructured":"Hinton, R. B. in Calcific Aortic Valve Disease (ed Elena Aikawa) Chapter 7. 173\u2013203. https:\/\/doi.org\/10.5772\/55506 (InTech, Europe, Rijeka, Croatia, 2013).","DOI":"10.5772\/55506"},{"key":"89164_CR46","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1161\/01.CIR.0000157137.59691.0B","volume":"111","author":"MB Lewin","year":"2005","unstructured":"Lewin, M. B. & Otto, C. M. The bicuspid aortic valve: adverse outcomes from infancy to old age. Circulation 111, 832\u2013834 (2005).","journal-title":"Circulation"},{"key":"89164_CR47","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/j.jacc.2008.12.023","volume":"53","author":"RB Hinton","year":"2009","unstructured":"Hinton, R. B. et al. Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J. Am. Coll. Cardiol. 53, 1065 (2009).","journal-title":"J. Am. Coll. Cardiol."},{"key":"89164_CR48","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s00439-006-0316-9","volume":"121","author":"LJ Martin","year":"2007","unstructured":"Martin, L. J. et al. Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Human Gen. 121, 275\u2013284 (2007) (PMID: 17203300).","journal-title":"Human Gen."},{"key":"89164_CR49","doi-asserted-by":"publisher","DOI":"10.5339\/ahcsps.2011.5309","author":"MP Hitz","year":"2011","unstructured":"Hitz, M. P., Brand, T. & Andelfinger, G. Genetic regulation of heart valve development: clinical implications. Aswan Heart Centre Sci. Pract. Ser. https:\/\/doi.org\/10.5339\/ahcsps.2011.5309 (2011).","journal-title":"Aswan Heart Centre Sci. Pract. Ser."},{"key":"89164_CR50","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1161\/CIRCRESAHA.116.309306","volume":"120","author":"L Simard","year":"2017","unstructured":"Simard, L. et al. Sex-related discordance between aortic valve calcification and hemodynamic severity of aortic stenosis. Circ. Res. 120, 681\u2013691. https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.309306 (2017).","journal-title":"Circ. Res."},{"key":"89164_CR51","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.015610","author":"M Voisine","year":"2020","unstructured":"Voisine, M. et al. Age, sex, and valve phenotype differences in fibro-calcific remodeling of calcified aortic valve. J. Am. Heart. Assoc. https:\/\/doi.org\/10.1161\/JAHA.119.015610 (2020).","journal-title":"J. Am. Heart. Assoc."},{"key":"89164_CR52","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.acvd.2012.02.013","volume":"105","author":"R Henaine","year":"2012","unstructured":"Henaine, R., Roubertie, F., Vergnat, M. & Ninet, J. Valve replacement in children: a challenge for a whole life. Arch. Cardiovasc. Dis. 105, 517\u2013528 (2012) (PMID: 23062483).","journal-title":"Arch. Cardiovasc. Dis."},{"key":"89164_CR53","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.tig.2003.11.004","volume":"20","author":"J Myllyharju","year":"2004","unstructured":"Myllyharju, J. & Kivirikko, K. I. Collagens, modifying enzymes and their mutations in humans, flies and worms. TRENDS Gen. 20, 33\u201343 (2004) (PMID: 14698617).","journal-title":"TRENDS Gen."},{"key":"89164_CR54","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1042\/BJ20151169","volume":"473","author":"J Bella","year":"2016","unstructured":"Bella, J. Collagen structure: new tricks from a very old dog. Biochem. J. 473, 1001\u20131025 (2016) (PMID: 27060106).","journal-title":"Biochem. J."},{"key":"89164_CR55","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1007\/s00726-008-0073-2","volume":"35","author":"SM Krane","year":"2008","unstructured":"Krane, S. M. The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of collagens. Amino Acids 35, 703\u2013710 (2008) (PMID: 18431533).","journal-title":"Amino Acids"},{"key":"89164_CR56","doi-asserted-by":"publisher","first-page":"14637","DOI":"10.1021\/bi020574b","volume":"41","author":"WJ Wedemeyer","year":"2002","unstructured":"Wedemeyer, W. J., Welker, E. & Scheraga, H. A. Proline cis-trans isomerization and protein folding. Biochemistry 41, 14637\u201314644 (2002) (PMID: 12475212).","journal-title":"Biochemistry"},{"key":"89164_CR57","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1158\/1078-0432.CCR-17-1707","volume":"24","author":"L Tang","year":"2018","unstructured":"Tang, L. et al. Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma. Clin. Cancer Res. 24, 474\u2013485 (2018) (PMID: 29084919).","journal-title":"Clin. Cancer Res."},{"key":"89164_CR58","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3109\/10409231003627991","volume":"45","author":"KL Gorres","year":"2010","unstructured":"Gorres, K. L. & Raines, R. T. Prolyl 4-hydroxylase. Crit. Rev. Biochem. Mol. Biol. 45, 106\u2013124 (2010).","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"89164_CR59","doi-asserted-by":"publisher","first-page":"5989","DOI":"10.1074\/jbc.273.11.5989","volume":"273","author":"P Annunen","year":"1998","unstructured":"Annunen, P., Autio-Harmainen, H. & Kivirikko, K. I. The novel type II prolyl 4-hydroxylase is the main enzyme form in chondrocytes and capillary endothelial cells, whereas the type I enzyme predominates in most cells. J. Biol. Chem. 273, 5989\u20135992 (1998) (PMID: 9497309).","journal-title":"J. Biol. Chem."},{"key":"89164_CR60","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/978-94-017-9153-3_9","volume":"819","author":"S Hamaia","year":"2014","unstructured":"Hamaia, S. & Farndale, R. W. Integrin recognition motifs in the human collagens. Adv. Exp. Med. Biol. 819, 127\u2013142 (2014).","journal-title":"Adv. Exp. Med. Biol."},{"key":"89164_CR61","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1039\/C9BM00186G","volume":"7","author":"M Ilamaran","year":"2019","unstructured":"Ilamaran, M. et al. A self-assembly and higher order structure forming triple helical protein as a novel biomaterial for cell proliferation. Biomater. Sci. 7, 2191\u20132199 (2019).","journal-title":"Biomater. Sci."},{"key":"89164_CR62","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.actbio.2017.10.035","volume":"65","author":"N Davidenko","year":"2018","unstructured":"Davidenko, N. et al. Selecting the correct cellular model for assessing of the biological response of collagen-based biomaterials. Acta Biomater. 65, 88\u2013101 (2018) (PMID: 25023172).","journal-title":"Acta Biomater."},{"key":"89164_CR63","doi-asserted-by":"publisher","first-page":"16761","DOI":"10.1074\/jbc.M301370200","volume":"278","author":"B Leitinger","year":"2003","unstructured":"Leitinger, B. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2 identification of collagen binding sites in DDR2. J. Biol. Chem. 278, 16761\u201316769 (2003).","journal-title":"J. Biol. Chem."},{"key":"89164_CR64","doi-asserted-by":"publisher","first-page":"7645","DOI":"10.1074\/jbc.RA118.002200","volume":"293","author":"KH Sipil\u00e4","year":"2018","unstructured":"Sipil\u00e4, K. H. et al. Proline hydroxylation in collagen supports integrin binding by two distinct mechanisms. J. Biol. Chem. 293, 7645\u20137658 (2018) (PMCID: PMC5961056).","journal-title":"J. Biol. Chem."},{"key":"89164_CR65","volume-title":"I Domain Integrins 127\u2013142","author":"S Hamaia","year":"2014","unstructured":"Hamaia, S. & Farndale, R. W. I Domain Integrins 127\u2013142 (Springer, Berlin, 2014) (PMID: 25023172)."},{"key":"89164_CR66","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-59028-w","volume":"10","author":"B Wasinski","year":"2020","unstructured":"Wasinski, B. et al. Discoidin domain receptors, DDR1b and DDR2, promote tumour growth within collagen but ddr1b suppresses experimental lung metastasis in HT1080 xenografts. Sci. Rep. 10, 1\u201321 (2020).","journal-title":"Sci. Rep."},{"key":"89164_CR67","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1242\/jcs.180992","volume":"129","author":"C Zeltz","year":"2016","unstructured":"Zeltz, C. & Gullberg, D. The integrin-collagen connection: a glue for tissue repair?. J. Cell Sci. 129, 653\u2013664. https:\/\/doi.org\/10.1242\/jcs.180992 (2016).","journal-title":"J. Cell Sci."},{"key":"89164_CR68","doi-asserted-by":"publisher","first-page":"46197","DOI":"10.1074\/jbc.M204029200","volume":"277","author":"Y Miura","year":"2002","unstructured":"Miura, Y., Takahashi, T., Jung, S. M. & Moroi, M. Analysis of the interaction of platelet collagen receptor glycoprotein VI (GPVI) with collagen: a dimeric form of GPVI, but not the monomeric form, shows affinity to fibrous collagen. J. Biol. Chem. 277, 46197\u201346204. https:\/\/doi.org\/10.1074\/jbc.M204029200 (2002).","journal-title":"J. Biol. Chem."},{"key":"89164_CR69","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1136\/hrt.74.6.641","volume":"74","author":"JR O'Brien","year":"1995","unstructured":"O\u2019Brien, J. R., Etherington, M. D., Brant, J. & Watkins, J. Decreased platelet function in aortic valve stenosis: high shear platelet activation then inactivation. Heart 74, 641\u2013644. https:\/\/doi.org\/10.1136\/hrt.74.6.641 (1995).","journal-title":"Heart"},{"key":"89164_CR70","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-809847-9.00005-2","volume-title":"Type V Collagen. Biochemistry of Collagen, Laminins and Elastin","author":"DJ Leeming","year":"2016","unstructured":"Leeming, D. J. & Karsdal, M. A. Type V Collagen. Biochemistry of Collagen, Laminins and Elastin (Academic Press, 2016). https:\/\/doi.org\/10.1016\/B978-0-12-809847-9.00005-2."},{"key":"89164_CR71","doi-asserted-by":"crossref","unstructured":"Montesi, S. B., D\u00e9sog\u00e8re, P., Fuchs, B. C. & Caravan, P. in Journal of Clinical Investigation vol. 129 24\u201333 (American Society for Clinical Investigation, 2019).","DOI":"10.1172\/JCI122132"},{"key":"89164_CR72","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1002\/ar.24133","volume":"303","author":"H Riley","year":"2019","unstructured":"Riley, H. & Bradshaw, A. The influence of the extracellualr matrix in inflammation: findings from the SPARC null mouse. Anat. Rec. 303, 1624\u20131629. https:\/\/doi.org\/10.1002\/ar.24133 (2019).","journal-title":"Anat. Rec."},{"key":"89164_CR73","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1161\/01.RES.0000141146.95728.da","volume":"95","author":"EJ Armstrong","year":"2004","unstructured":"Armstrong, E. J. et al. Heart valve development: endothelial cell signaling and differentiation. Circ. Res. 95, 459\u2013470. https:\/\/doi.org\/10.1161\/01.RES.0000141146.95728.da (2004).","journal-title":"Circ. Res."},{"key":"89164_CR74","unstructured":"Rabkin-Aikawa, E., Farber, M., Aikawa, M. & Schoen, F. J. in Journal of Heart Valve Disease Vol. 13 841\u2013847 (2004)."},{"key":"89164_CR75","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/S0039-6109(05)70111-0","volume":"80","author":"T Razek","year":"2000","unstructured":"Razek, T., Olthoff, K. & Reilly, P. M. Issues in potential organ donor management. Surg. Clin. North Am. 80, 1021\u20131032. https:\/\/doi.org\/10.1016\/S0039-6109(05)70111-0 (2000).","journal-title":"Surg. Clin. North Am."},{"key":"89164_CR76","doi-asserted-by":"crossref","unstructured":"Siebelink, M. J., Albers, M. J. I. J., Roodbol, P. F. & Van De Wiel, H. B. M. in Transplant International Vol. 25 265\u2013271 (John Wiley & Sons, Ltd, 2012).","DOI":"10.1111\/j.1432-2277.2011.01407.x"},{"key":"89164_CR77","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.athoracsur.2014.07.027","volume":"99","author":"XS Deng","year":"2015","unstructured":"Deng, X. S. et al. Adult aortic valve interstitial cells have greater responses to toll-like receptor 4 stimulation. Ann. Thorac. Surg. 99, 62\u201371. https:\/\/doi.org\/10.1016\/j.athoracsur.2014.07.027 (2015).","journal-title":"Ann. Thorac. Surg."},{"key":"89164_CR78","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1089\/ten.tec.2014.0589","volume":"21","author":"B Duan","year":"2015","unstructured":"Duan, B., Hockaday, L. A., Das, S., Xu, C. & Butcher, J. T. Comparison of mesenchymal stem cell source differentiation toward human pediatric aortic valve interstitial cells within 3D engineered matrices. Tissue Eng. Part C Methods 21, 795\u2013807. https:\/\/doi.org\/10.1089\/ten.tec.2014.0589 (2015).","journal-title":"Tissue Eng. Part C Methods"},{"key":"89164_CR79","doi-asserted-by":"publisher","first-page":"S153","DOI":"10.1542\/peds.2012-0055I","volume":"129","author":"K Williams","year":"2012","unstructured":"Williams, K. et al. Standard 6: age groups for pediatric trials. Pediatrics 129, S153\u2013S160. https:\/\/doi.org\/10.1542\/peds.2012-0055I (2012).","journal-title":"Pediatrics"},{"key":"89164_CR80","doi-asserted-by":"publisher","first-page":"25","DOI":"10.2144\/000112517","volume":"43","author":"TJ Collins","year":"2007","unstructured":"Collins, T. J. ImageJ for microscopy. Biotechniques 43, 25\u201330 (2007) (PMID: 17936939).","journal-title":"Biotechniques"},{"key":"89164_CR81","doi-asserted-by":"publisher","first-page":"016007","DOI":"10.1117\/1.JBO.19.1.016007","volume":"19","author":"JS Bredfeldt","year":"2014","unstructured":"Bredfeldt, J. S. et al. Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer. J. Biomed. Opt. 19, 016007 (2014).","journal-title":"J. Biomed. Opt."},{"key":"89164_CR82","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1074\/mcp.M800518-MCP200","volume":"8","author":"RW Sprung","year":"2009","unstructured":"Sprung, R. W. et al. Equivalence of protein inventories obtained from formalin-fixed paraffin-embedded and frozen tissue in multidimensional liquid chromatography-tandem mass spectrometry shotgun proteomic analysis. Mol. Cell. Proteom. 8, 1988\u20131998 (2009) (PMCID: PMC2722776).","journal-title":"Mol. Cell. Proteom."},{"key":"89164_CR83","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1021\/ac026117i","volume":"75","author":"J Rappsilber","year":"2003","unstructured":"Rappsilber, J., Ishihama, Y. & Mann, M. Stop and go extraction tips for matrix-assisted laser desorption\/ionization, nanoelectrospray, and LC\/MS sample pretreatment in proteomics. Anal. Chem. 75, 663\u2013670 (2003).","journal-title":"Anal. Chem."},{"key":"89164_CR84","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1038\/nprot.2016.136","volume":"11","author":"S Tyanova","year":"2016","unstructured":"Tyanova, S., Temu, T. & Cox, J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat. Protoc. 11, 2301\u20132319 (2016).","journal-title":"Nat. Protoc."},{"key":"89164_CR85","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nmeth.3901","volume":"13","author":"S Tyanova","year":"2016","unstructured":"Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote) omics data. Nat. Methods 13, 731 (2016).","journal-title":"Nat. Methods"},{"key":"89164_CR86","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner, M. et al. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25\u201329 (2000).","journal-title":"Nat. Genet."},{"key":"89164_CR87","doi-asserted-by":"publisher","first-page":"D330","DOI":"10.1093\/nar\/gky1055","volume":"47","author":"C Gene Ontology","year":"2019","unstructured":"Gene Ontology, C. The gene ontology resource: 20 years and still GOing strong. Nucl. Acids Res. 47, D330\u2013D338 (2019).","journal-title":"Nucl. Acids Res."},{"key":"89164_CR88","doi-asserted-by":"publisher","first-page":"D419","DOI":"10.1093\/nar\/gky1038","volume":"47","author":"H Mi","year":"2019","unstructured":"Mi, H., Muruganujan, A., Ebert, D., Huang, X. & Thomas, P. D. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucl. Acids Res. 47, D419\u2013D426 (2019).","journal-title":"Nucl. Acids Res."},{"key":"89164_CR89","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/S0076-6879(06)11009-5","volume":"411","author":"AI Saeed","year":"2006","unstructured":"Saeed, A. I. et al. TM4 microarray software suite. Methods Enzymol. 411, 134\u2013193 (2006).","journal-title":"Methods Enzymol."},{"key":"89164_CR90","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1194\/jlr.D200020-JLR200","volume":"43","author":"YR Su","year":"2002","unstructured":"Su, Y. R., Linton, M. F. & Fazio, S. Rapid quantification of murine ABC mRNAs by real time reverse transcriptase-polymerase chain reaction. J. Lipid Res. 43, 2180\u20132187. https:\/\/doi.org\/10.1194\/jlr.D200020-JLR200 (2002).","journal-title":"J. Lipid Res."},{"key":"89164_CR91","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","volume":"55","author":"SA Bustin","year":"2009","unstructured":"Bustin, S. A. et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55, 611\u2013622. https:\/\/doi.org\/10.1373\/clinchem.2008.112797 (2009).","journal-title":"Clin. Chem."},{"key":"89164_CR92","doi-asserted-by":"publisher","first-page":"D442","DOI":"10.1093\/nar\/gky1106","volume":"47","author":"Y Perez-Riverol","year":"2019","unstructured":"Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucl. Acids Res. 47, D442\u2013D450 (2019).","journal-title":"Nucl. Acids Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89164-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89164-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89164-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T05:12:19Z","timestamp":1675228339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89164-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,7]]},"references-count":92,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["89164"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-89164-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,7]]},"assertion":[{"value":"15 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9751"}}