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- Title
Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity.
- Authors
Lother, Achim; Bergemann, Stella; Kowalski, Jessica; Huck, Michael; Gilsbach, Ralf; Bode, Christoph; Hein, Lutz
- Abstract
Aim Anthracyclines such as doxorubicin are widely used in cancer therapy but their use is limited by cardiotoxicity. Up to date there is no established strategy for the prevention of anthracyclin-induced heart failure. In this study, we evaluated the role of the cardiac myocyte mineralocorticoid receptor (MR) during doxorubicin-induced cardiotoxicity Methods and results A single high-dose or repetitive low-dose doxorubicin administration lead to markedly reduced left ventricular function in mice. Treatment with the MR antagonist eplerenone prevented doxorubicin-induced left ventricular dysfunction. In order to identify the cell types and molecular mechanisms involved in this beneficial effect we used a mouse model with cell type-specific MR deletion in cardiac myocytes. Cardiac myocyte MR deletion largely reproduced the effect of pharmacological MR inhibition on doxorubicin-induced cardiotoxicity. RNAseq from isolated cardiac myocytes revealed a repressive effect of doxorubicin on gene expression which was prevented by MR deletion. Conclusions We show here that (i) eplerenone prevents doxorubicin-induced left ventricular dysfunction in mice, and (ii) this beneficial effect is related to inhibition of MR in cardiac myocytes. Together with present clinical trial data our findings suggest that MR antagonism may be appropriate for the prevention of doxorubicin-induced cardiotoxicity.
- Subjects
HEALTH outcome assessment; DRUG efficacy; ANTHRACYCLINES; CANCER treatment; HEART failure; PREVENTION
- Publication
Cardiovascular Research, 2018, Vol 114, Issue 2, p282
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvx078