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Elastic fiber fragmentation (<jats:styled-content style=\"fixed-case\">EFF<\/jats:styled-content>) is a hallmark of <jats:styled-content style=\"fixed-case\">AVD<\/jats:styled-content>, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The <jats:italic>Emilin1\u2010<\/jats:italic>deficient mouse (<jats:italic>Emilin1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) is a model of latent <jats:styled-content style=\"fixed-case\">AVD<\/jats:styled-content>, characterized by activated <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b2\/<jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>\/p\u2010Erk signaling and upregulated elastase activity. <jats:italic>Emilin1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> aortic valves demonstrate early <jats:styled-content style=\"fixed-case\">EFF<\/jats:styled-content> and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12\u201314\u00a0months) <jats:italic>Emilin1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice were treated with refametinib (<jats:styled-content style=\"fixed-case\">RDEA<\/jats:styled-content>\u2010119, <jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>1\/2 inhibitor), doxycycline (elastase inhibitor), or G6\u201031 (anti\u2010<jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A mouse antibody) for 4\u00a0weeks. Refametinib\u2010 and doxycycline\u2010treated <jats:italic>Emilin1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice markedly reduced <jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>\/p\u2010Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u20102, and <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u20109 activation, and abrogated macrophage and neutrophil infiltration in <jats:italic>Emilin1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> aortic valves. <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>seq analysis was performed in aortic valve tissue from adult (4\u00a0months) and aged (14\u00a0months) <jats:italic>Emilin1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and age\u2010matched wild\u2010type control mice, and demonstrated upregulation of genes associated with <jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>\/p\u2010Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1\/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt <jats:styled-content style=\"fixed-case\">AVD<\/jats:styled-content> progression<\/jats:p>","DOI":"10.14814\/phy2.13152","type":"journal-article","created":{"date-parts":[[2017,3,8]],"date-time":"2017-03-08T01:10:26Z","timestamp":1488935426000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of MAPK\u2010Erk pathway in\u00a0vivo attenuates aortic valve disease processes in Emilin1\u2010deficient mouse model"],"prefix":"10.14814","volume":"5","author":[{"given":"Charu","family":"Munjal","sequence":"first","affiliation":[{"name":"Divisions of Cardiology Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil G.","family":"Jegga","sequence":"additional","affiliation":[{"name":"Biomedical Informatics Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy M.","family":"Opoka","sequence":"additional","affiliation":[{"name":"Divisions of Cardiology Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Stoilov","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology Washington University School of Medicine St. Louis Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell A.","family":"Norris","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Medical University of South Carolina Charleston South Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig J.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Pre\u2010Clinical Innovation National Center for Advancing Translational Sciences National Institutes of Health Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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