Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss‐of‐function 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 II (Ang II ) to model the role of calcineurin in CH in adulthood. Ang II ‐induced 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 II ‐induced CH. Surprisingly, cardiac‐specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced Ang II ‐induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that Ang II ‐induced expression of Tgfβ family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac‐specific calcineurin deletion. These results show that Ang II induces a direct, calcineurin‐dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.