{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:20:44Z","timestamp":1773307244633,"version":"3.50.1"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,10,16]]},"abstract":"\n Background<\/jats:title>\n \n Aortic valve sclerosis (\n AVS<\/jats:styled-content>\n c), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65\u00a0years. In vitro and ex\u00a0vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that\n AVS<\/jats:styled-content>\n c is reversible. In this study, we characterized the underlying changes in the extracellular matrix architecture and valve interstitial cell activation in AVSc and tested in\u00a0vitro and in\u00a0vivo the activity of a clinically approved SOD (superoxide dismutase) mimic and redox\u2010active drug MnTnBu\n OE<\/jats:styled-content>\n \u20102\u2010PyP\n 5+<\/jats:sup>\n (\n BMX<\/jats:styled-content>\n \u2010001).\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n After receiving informed consent, samples from patients with\n AVS<\/jats:styled-content>\n c, AV stenosis, and controls were collected. Uniaxial mechanical stimulation and in\u00a0vitro studies on human valve interstitial cells were performed. An angiotensin\n II<\/jats:styled-content>\n chronic infusion model was used to impose\n AV<\/jats:styled-content>\n thickening and remodeling. We characterized extracellular matrix structures by small\u2010angle light scattering, scanning electron microscopy, histology, and mass spectrometry. Diseased human valves showed altered collagen fiber alignment and ultrastructural changes in\n AVS<\/jats:styled-content>\n c, accumulation of oxidized cross\u2010linking products in AV stenosis, and reversible expression of extracellular matrix regulators ex\u00a0vivo. We demonstrated that MnTnBu\n OE<\/jats:styled-content>\n \u20102\u2010PyP\n 5+<\/jats:sup>\n inhibits human valve interstitial cell activation and extracellular matrix remodeling in a murine model (C57\n BL<\/jats:styled-content>\n \/6J) of\n AVS<\/jats:styled-content>\n c by electron microscopy and histology.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n AVS<\/jats:styled-content>\n c is associated with architectural remodeling despite marginal effects on the mechanical properties in both human and mice. MnTnBu\n OE<\/jats:styled-content>\n \u20102\u2010PyP\n 5+<\/jats:sup>\n controls\n AV<\/jats:styled-content>\n thickening in a murine model of\n AVS<\/jats:styled-content>\n c. Because this compound has been approved recently for clinical use, this work could shift the focus for the treatment of calcific AV disease, moving from AV stenosis to an earlier presentation (\n AVS<\/jats:styled-content>\n c) that could be more responsive to medical therapies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.117.007861","type":"journal-article","created":{"date-parts":[[2018,10,3]],"date-time":"2018-10-03T09:02:44Z","timestamp":1538557364000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Porphyrin\u2010Based SOD Mimic MnTnBuOE\u20102\u2010PyP\n 5+<\/sup>\n Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis"],"prefix":"10.1161","volume":"7","author":[{"given":"Wanda","family":"Anselmo","sequence":"first","affiliation":[{"name":"University of Pennsylvania Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuela","family":"Branchetti","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan B.","family":"Grau","sequence":"additional","affiliation":[{"name":"Ottawa Heart Institute Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gen","family":"Li","sequence":"additional","affiliation":[{"name":"Columbia University New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salma","family":"Ayoub","sequence":"additional","affiliation":[{"name":"Texas University at Austin TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric K.","family":"Lai","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Rioux","sequence":"additional","affiliation":[{"name":"The Valley Hospital Ridgewood NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artak","family":"Tovmasyan","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine Durham NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline H.","family":"Fortier","sequence":"additional","affiliation":[{"name":"Ottawa Heart Institute Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S.","family":"Sacks","sequence":"additional","affiliation":[{"name":"Texas University at Austin TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Batinic\u2010Haberle","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine Durham NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley L.","family":"Hazen","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Cleveland OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Levy","sequence":"additional","affiliation":[{"name":"The Children's Hospital of Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Columbia University New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2010.10.012"},{"key":"e_1_3_2_3_2","first-page":"2387","volume-title":"Calcific Aortic Valve Disease: A Consensus Summary From the Alliance of Investigators on Calcific Aortic Valve Disease","author":"Yutzey KE","year":"2014","unstructured":"Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, Hofmann Bowman MA, Mortlock DP, Rogers MB, Sadeghi MM, Aikawa E. 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