Mitochondrial respiratory complexes, excitation-contraction coupling and mTOR signaling transcriptional programs are dysregulated in cardiometabolic HFpEF

Abstract

Heart failure is a leading cause of death and disability worldwide. Nearly, half of the cases correspond to HF with preserved ejection fraction (HFpEF), which is predicted to become the most prevalent form of HF in the forthcoming years. In this study, we performed a bulk RNA-seq assay to study the transcriptomic profiles of the hearts of HFpEF mice. HFpEF animals consisted in C57BL/6 mic that were fed a high-fat diet and exposed to L-NAME in the drinking water during five or eight weeks. Controls received a standard chow diet. Differential expression analysis yielded 1535 differentially expressed genes in HFpEF hearts relative to controls. 71 out of 78 DEGs contained in the GO-CC "Mitochondrial Inner Membrane (GO:0005743)" were found to be down-regulated, mostly affecting respiratory complexes I, III, IV and V in a time-dependent manner. Overrepresentation analyses also suggested that the mTOR signaling cascade is switched on, while "Diabetic Cardiomyopathy", "Cardiac Muscle Contraction" and "Cytoskeleton in Muscle Cells" KEGG pathways were detected to be affected, probably pointing at excitation-contraction coupling impairment. In summary, the transcriptomic program of the HFpEF hearts consisted in a widespread downregulation of the expression of the subunits of mitochondrial respiratory complexes, upregulation of mTOR signaling and deregulation of the genes related to the excitation-contraction coupling.