[Prevention of heart failure by the antagonisation of the mineralocorticoid receptor in the context of metabolic syndrome : an integrative study of the phenome, transcriptome and miRNome]. (Doctoral thesis)

Original title: Prévention de l'insuffisance cardiaque par l'antagonisation du récepteur des minéralocorticoïdes dans un contexte de syndrome métabolique : une étude intégrative du phénome, du transcriptiome et du miRNOme.
Mineralocorticoid Receptor Antagonists (MRA) are clinically beneficial in individuals with chronic heart failure (HF). One of the major risk factors for HF, the metabolic syndrome (MetS), has been also reported to be associated with increased aldosterone production and excessive MR activation. In this context, we hypothesized that the use of MRA could be applied to target the MetS features and prevent the subsequent progression towards HF. In this project, Spontaneously Hypertensive Heart failure rats (SHHF) carrying or not a mutation in the leptin receptor (« cp ») leading to MetS development (SHHFcp/cp and SHHF+/+respectively) were used as experimental model. Animals from both genotypes were given either the selective MRA (Eplerenone, Eple) or placebo from 1.5 to 12.5 months of age and their metabolic and cardiovascular parameters were regularly monitored. The molecular functions altered in the heart and visceral adipose tissues as MetS develops and progresses towards HF as well as those modulated by Eple action were characterized by the analysis of animal’s transcriptome and miRNome. Our data showed that SHHFcp/cp exbiting MetS developed at 12.5 months of age eccentric cardiac hypertrophy associated with left ventricular (LV) dilatation and reduced ejection fraction (EF) as compared to SHHF+/+. While Eple did not induced differences in metabolic and cardiovascular phenotypes in SHHF+/+ rats, Eple-SHHFcp/cp had lower body weight gain and less dyslipidemia. Without effects on blood pressure (BP) and adipose transcriptome and miRNome, Eple-SHHFcp/cp rats had lower LV dilatation and hypertrophy, higher ejection fraction, isovolumic relaxation time and E/A ratio. Transcriptome and miRNome analysis of cardiac tissues revealed that Eple markedly reduced the expression of several genes involved in cardiac remodeling and inflammatory processes and increased the expression of genes related to cardiac fatty acid oxidation and metabolism. The integration and the bioinformatic exploration of transcriptome and miRNome expression profiles allowed the construction of gene regulatory networks potentially involved in the physiopathological mechanisms occuring in the SHHFcp/cp rats and those impacted by the treatment. Altogether, our data demonstrated that treatment with Eple during MetS development attenuated SHHFcp/cp weight gain and dyslipidemia contributing to the amelioration of their cardiac structural and functional parameters. Interestingly, those beneficial cardioprotective effects were obtained via mechanisms independent of BP lowering, the analysis of cardiac transcriptome/miRnome revealed that Eple may have acted by depressing cardiac remodeling and inflammatory processes and restoring the function of fatty acid metabolism in the myocardium.