{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:25:09Z","timestamp":1793262309976,"version":"4.5.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05; fold-change &gt;1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-\u03b22 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-\u03b2 signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2\/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt\/\u03b2-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-\u03b22 increased \u03b2-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-\u03b22 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>These data support a new disease framework whereby activation of TGF-\u03b22, bone morphogenetic protein 4, Wnt\/\u03b2-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.114.000921","type":"journal-article","created":{"date-parts":[[2015,3,27]],"date-time":"2015-03-27T13:44:03Z","timestamp":1427463843000},"page":"516-528","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":55,"title":["Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease"],"prefix":"10.1161","volume":"8","author":[{"given":"Nassir M.","family":"Thalji","sequence":"first","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Hagler","sequence":"additional","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Casaclang-Verzosa","sequence":"additional","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asha A.","family":"Nair","sequence":"additional","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh M.","family":"Suri","sequence":"additional","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D.","family":"Miller","sequence":"additional","affiliation":[{"name":"From the Department of Surgery, Division of Cardiovascular Surgery (N.M.T., M.A.H., H.Z., G.C.-V., R.M.S., J.D.M.), Department of Biomedical Statistics and Informatics (A.A.N.), and Department of Physiology and Biomedical Engineering (J.D.M.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199907013410101"},{"key":"e_1_3_3_3_2","first-page":"637","article-title":"Pathology of the myxomatous mitral value. 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