Identification of metabolic targets and signalling pathways involved in the pathophysiology of heart failure with preserved ejection fraction

Abstract

Heart failure (HF) with preserved ejection fraction (pEF) is a public health burden with no effective treatment. Our team developed a new transgenic rat model of HFpEF [Tgβ 3 –overexpressing the human (h) β 3 –adrenoreceptor (β 3 -AR) in endothelium]. The role of β3-AR remain contradictory in HF. β 3 -AR is known to induce a negative inotropic effect and vasodilation via the nitric oxide ( . NO) pathway and it also modulates lipolysis in adipose tissue. We aimed to evaluate the mechanisms involved in HFpEF development with a particular focus on β 3 -AR pathway and cardiac metabolism. Transcriptome analysis was performed on left ventricle (LV) tissue from 45 weeks old rats. Among 241 altered genes, we focused on metabolic targets and β 3 -AR pathway by RT-qPCR, western-blot and functional analysis. NO production in aorta is evaluated with NO spin trapping and analysis by electron paramagnetic resonance (EPR). Overexpression of hβ 3 -AR in endothelium leads to a reduction of Nos3 mRNA expression (−70% P < 0.05 vs WT) and a decrease in protein expression (−19% P < 0.05 vs WT) indicating an alteration of the NO pathway. Surprisingly, evaluation of vascular . NO production revealed an increase in NO production in Tgβ 3 rats. Transcriptome analysis revealed 10 altered metabolic genes. Evaluation of these targets revealed at least one potential target of interest (metabolic target 1–MT1). MT1 mRNA and protein levels were increased in Tgβ 3 rats (+ 62% and + 67% P < 0.05 vs WT, respectively). These modifications were associated with an increase in the phospho-AMPK to AMPK ratio (+ 104% P < 0.05 vs WT), a metabolic sensor that plays a regulatory role in the energetic homeostasis in heart. Our results indicate that HFpEF development is associated with an alteration of the NO pathway and metabolic alteration. Functional analysis of MT1 is ongoing and results might open new therapeutic avenues.