{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T21:12:09Z","timestamp":1762809129610,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"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":["R00-HL092235","R01-HL111121"],"award-info":[{"award-number":["R00-HL092235","R01-HL111121"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> While a small number of studies suggest that oxidative stress has an influential role in fibrocalcific aortic valve disease (FCAVD), the roles of specific antioxidant enzymes in progression of this disease remain poorly understood. Here, we focused on selectively altering mitochondrial-derived oxidative stress\u2014which has been shown to alter progression of a myriad of age-associated diseases\u2014on the progression of molecular and phenotypic drivers of FCAVD.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We generated low-density lipoprotein receptor-deficient, Apolipoprotein B100-only mice (LA) that were either haploinsufficient for MnSOD (<jats:italic>LA-MnSOD<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) or genetically overexpressing MnSOD (<jats:italic>LA-MnSOD<\/jats:italic><jats:sup><jats:italic>Tg<\/jats:italic>\/0<\/jats:sup>). After 6 months of Western diet feeding, mice underwent echocardiography to assess valvular and cardiac function and tissues were harvested. Quantitative-RT PCR, immunohistochemistry, and histopathology were used to measure changes in molecular pathways related to oxidative stress, calcification, and fibrosis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> While reductions in MnSOD increased oxidative stress, there was not an overt phenotypic effect of MnSOD deficiency on valvular and cardiac function in <jats:italic>LA-MnSOD<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice. While markers of canonical bone morphogenetic protein signaling tended to increase in valve tissue from <jats:italic>LA-MnSOD<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> (e.g., p-SMAD1\/5\/8 and osterix), we did not observe statistically significant increases in osteogenic signaling. We did, however, observe highly significant reductions in expression of osteopontin, which were associated with significant increases in calcium burden in <jats:italic>LA-MnSOD<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice. Reciprocally, genetically increasing MnSOD did not preserve valve function in <jats:italic>LA-MnSOD<\/jats:italic><jats:sup><jats:italic>Tg<\/jats:italic>\/0<\/jats:sup>, but we did observe slight reductions in p-SMAD1\/5\/8 levels compared to their <jats:italic>non<\/jats:italic>-transgenic littermates. Interestingly, overexpression of MnSOD dramatically increased expression of osteopontin in valve tissue from <jats:italic>LA-MnSOD<\/jats:italic><jats:sup><jats:italic>Tg<\/jats:italic>\/0<\/jats:sup> mice, but was not sufficient to attenuate calcium burden when compared to their <jats:italic>LA-MnSOD<\/jats:italic><jats:sup>0\/0<\/jats:sup> littermates.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Collectively, this study demonstrates that maintenance of mitochondrial antioxidant capacity is important in preventing accelerated disease progression in a mouse model of FCAVD, but that effectively altering mitochondrial antioxidant capacity as a monotherapeutic approach to slow key histopathological and molecular drivers of FCAVD remains biologically and therapeutically challenging.<\/jats:p>","DOI":"10.3389\/fcvm.2021.694881","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T04:33:03Z","timestamp":1624509183000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Effects of Altering Mitochondrial Antioxidant Capacity on Molecular and Phenotypic Drivers of Fibrocalcific Aortic Valve Stenosis"],"prefix":"10.3389","volume":"8","author":[{"given":"Carolyn M.","family":"Roos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A.","family":"Hagler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace C.","family":"Verzosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runqing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise A.","family":"Oehler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arman","family":"Arghami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan D.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/s0735-1097(96)00563-3","article-title":"Clinical factors associated with calcific aortic valve disease. 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