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

• Published in: The FEBS journal Vol. 286; no. 1; pp. 46 - 65
• Main Authors: Martínez‐Martínez, Sara, Lozano‐Vidal, Noelia, López‐Maderuelo, María Dolores, Jiménez‐Borreguero, Luis J., Armesilla, Ángel Luis, Redondo, Juan Miguel
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2019
• Subjects: Adults; Angiotensin; Angiotensin II; Animal models; Apoptosis; Blood pressure; Calcineurin; Calcineurin inhibitors; Cardiomyocytes; Cyclosporin A; Fibrosis; Gene expression; Heart; Hypertension; Hypertrophy; Liquid oxygen; Mice; Proteins; pro‐fibrotic genes; cyclosporin A; pro-fibrotic genes; angiotensin II; heart
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14718

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 (AngII) to model the role of calcineurin in CH in adulthood. AngII‐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 AngII‐induced CH. Surprisingly, cardiac‐specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII‐induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII‐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 AngII induces a direct, calcineurin‐dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity. Cardiac hypertrophy (CH) has evolved as a protective mechanism to cope with cardiac stress; however, in a pathological context it is a major risk factor for heart failure. Previous studies have shown that pathological CH can be induced by activation of calcineurin. Here, Juan Miguel Redondo and colleagues established a conditional knockout model for calcineurin function in adult mice, based on induction of calcineurin activation by angiotensin II and inhibition of its activity by cyclosporin A. They demonstrate that the pro‐hypertrophic effect of angiotensin II in cardiomyocytes is calcineurin‐dependent, while its effect on blood pressure is independent of calcineurin activity.