{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:25Z","timestamp":1790189965291,"version":"4.1.0"},"reference-count":20,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Calcific aortic valve disease, commonly manifesting as aortic stenosis, is a leading cause of mortality with no effective therapy. We previously identified CROT (carnitine O-octanoyltransferase) as a mediator of mitochondrial dysfunction and vascular calcification; however, its role in calcific aortic valve disease is unknown. We investigated whether CROT promotes calcific aortic valve disease progression through the release of procalcific mitochondria-derived extracellular vesicles (mitoEVs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Human valvular interstitial cells were isolated from aortic valves of patients with aortic stenosis (n=49; n=34 males, n=15 females). Calcification was induced with osteogenic medium and assessed by Alizarin red. Proteomics compared valvular interstitial cells cultured in normal medium or osteogenic medium following scramble or\n                      <jats:italic toggle=\"yes\">CROT<\/jats:italic>\n                      siRNA to define CROT-dependent pathways. Mitochondrial function was evaluated by Seahorse XF analysis (oxygen consumption rate) and morphology by MitoTracker staining. Extracellular vesicles were isolated by ultracentrifugation and characterized using NanoSight Pro. In vivo, aortic stenosis was induced by aortic valve wire injury in\n                      <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">Crot<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      (Sham, n=12; aortic valve wire injury, n=19) and\n                      <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">Crot<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      (aortic valve wire injury, n=23) mice. Disease progression was monitored by echocardiography, and calcification was visualized using OsteoSense680EX imaging.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      CROT silencing significantly reduced osteogenic medium\u2013induced calcification in valvular interstitial cells (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.05). Proteomics revealed alterations in mitochondria-associated proteins following siCROT. Osteogenic medium\u2013induced mitochondrial fragmentation and increased mitoEV release were attenuated by CROT silencing. Immunofluorescence revealed mitoEVs localized to calcified extracellular regions. In vivo, CROT deficiency reduced valvular calcification and attenuated aortic stenosis progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Osteogenic stress drives mitochondrial fragmentation and procalcific mitoEV release. CROT inhibition restores mitochondrial homeostasis, reduces mitoEV release and calcification, identifying CROT as a potential therapeutic strategy for calcific aortic valve disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324456","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:01:15Z","timestamp":1778144475000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Extracellular Vesicles Enhance Aortic Valve Calcification Via Carnitine O-Octanoyltransferase\u2014Brief Report"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4343-0321","authenticated-orcid":true,"given":"Rei","family":"Itagawa","sequence":"first","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2423-8172","authenticated-orcid":true,"given":"Takehito","family":"Okui","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9608-9553","authenticated-orcid":true,"given":"Yuto","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9117-1387","authenticated-orcid":true,"given":"Daiki","family":"Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-4251","authenticated-orcid":true,"given":"Cassandra L.","family":"Clift","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3923-9786","authenticated-orcid":true,"given":"Mark C.","family":"Blaser","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8075-6099","authenticated-orcid":true,"given":"Taku","family":"Kasai","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6431-5077","authenticated-orcid":true,"given":"Mandy E.","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7591-0362","authenticated-orcid":true,"given":"Marie","family":"Billaud","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Excellence in Vascular Biology (M.B., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-2079","authenticated-orcid":true,"given":"Masanori","family":"Aikawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."},{"name":"Department of Medicine, Center for Excellence in Vascular Biology (M.B., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."},{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA (M.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0929-3164","authenticated-orcid":true,"given":"Sasha A.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (R.I., T.O., T.T., Y.N., D.H., C.L.C., M.C.B., T.K., L.W., M.E.T., M.A., S.A.S., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."},{"name":"Department of Medicine, Center for Excellence in Vascular 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Thrombosis, and Vascular 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