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In these studies, loss\u2010of\u2010function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> (Ang<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>) to model the role of calcineurin in CH in adulthood. Ang<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\u2010induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for Ang<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\u2010induced CH. Surprisingly, cardiac\u2010specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced Ang<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\u2010induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that Ang<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\u2010induced expression of <jats:italic>Tgf\u03b2<\/jats:italic> family members and <jats:italic>Lox<\/jats:italic> was not inhibited by cyclosporin A but was markedly reduced by cardiac\u2010specific calcineurin deletion. These results show that Ang<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> induces a direct, calcineurin\u2010dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.<\/jats:p>","DOI":"10.1111\/febs.14718","type":"journal-article","created":{"date-parts":[[2018,12,7]],"date-time":"2018-12-07T14:11:42Z","timestamp":1544191902000},"page":"46-65","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice"],"prefix":"10.1111","volume":"286","author":[{"given":"Sara","family":"Mart\u00ednez\u2010Mart\u00ednez","sequence":"first","affiliation":[{"name":"Gene Regulation in Cardiovascular Remodeling and Inflammation Group Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid 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