Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity.

Détails

ID Serval
serval:BIB_CDEEFA5F5568
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity.
Périodique
Cardiovascular research
Auteur(s)
Hullin R., Métrich M., Sarre A., Basquin D., Maillard M., Regamey J., Martin D.
ISSN
1755-3245 (Electronic)
ISSN-L
0008-6363
Statut éditorial
Publié
Date de publication
01/02/2018
Peer-reviewed
Oui
Volume
114
Numéro
2
Pages
272-281
Langue
anglais
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Aldosterone/blood, Angiotensin-Converting Enzyme Inhibitors/pharmacology, Animals, Cardiotoxicity, Connective Tissue Growth Factor/metabolism, Disease Models, Animal, Doxorubicin, Enalapril/pharmacology, Eplerenone/pharmacology, Male, Mice, Inbred C57BL, Mice, Knockout, Mineralocorticoid Receptor Antagonists/pharmacology, Myocytes, Cardiac/drug effects, Myocytes, Cardiac/metabolism, Myocytes, Cardiac/pathology, Phosphatidylinositol 3-Kinase/metabolism, Primary Prevention/methods, Proto-Oncogene Proteins c-akt/metabolism, Receptor, Angiotensin, Type 1/metabolism, Receptors, Mineralocorticoid/genetics, Receptors, Mineralocorticoid/metabolism, Renin-Angiotensin System/drug effects, Signal Transduction/drug effects, TOR Serine-Threonine Kinases/metabolism, Ventricular Dysfunction, Left/chemically induced, Ventricular Dysfunction, Left/metabolism, Ventricular Dysfunction, Left/physiopathology, Ventricular Dysfunction, Left/prevention & control, Ventricular Function, Left/drug effects, Anthracyclines, CTGF, Enalapril, Eplerenone, mTOR
Pubmed
Web of science
Open Access
Oui
Création de la notice
19/10/2017 8:37
Dernière modification de la notice
20/08/2019 16:48
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