eplerenone and Cardiotoxicity

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.. 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.. 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.

Topics: Animals; Atrophy; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Eplerenone; Female; Fibrosis; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Clinical studies suggest beneficial effects of renin-angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity.. Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF.. Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotoxicity; Connective Tissue Growth Factor; Disease Models, Animal; Doxorubicin; Enalapril; Eplerenone; Male; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Primary Prevention; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin-Angiotensin System; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Function, Left