Disturbance of iron metabolism related genes in advanced heart failure

Abstract

Abstract Background/Introduction Heart failure (HF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. Iron is a nutrient required in all organ systems for various metabolic processes, such as mitochondrial function, oxygen transport, myocardial and skeletal muscle metabolism, among others. Maintaining iron homeostasis is essential for proper cardiac function since both iron deficiency and iron overload are associated with HF through complex mechanisms, such as ferroptosis. Purpose The aim of this study was to analyse the status of iron metabolism in hearts from patients with dilated (DCM) and ischemic cardiomyopathy (ICM) and its implication with the pathophysiology of the disease. Methods Cardiac tissue samples were used to evaluated transcriptome differences in genes involved iron metabolism by mRNA-sequencing (mRNA-seq; ICM, n=13; DCM, n=13; CNT, n=10). Furthermore, the miRNA implicated in the mRNA posttrasciptional regulation was studied through non-coding RNA-seq (ICM, n=22; DCM, n=20; CNT, n=8). Results We observed a decrease in iron import with SNX4 underexpression in ICM (FC=-1.28) and DCM (FC=-1.27) patients, p<0.05. While the export is reduced only in patients with MCD: HAMP is underexpresed (FC=-2.41, p<0.01) and its miRNA, miR-184, overexpressed (FC=2.77, p<0.01). We also found alterations in molecules of iron homeostasis and transporters of both aetiologies: IREB2 (ICM, FC=-1.27, p<0.05; DCM, FC=-1.48, p<0.001), STEAP3 (ICM, FC=-1.63, p<0.05; DCM, FC=-2.24, p<0.001), NOX4 (DCM, FC=1.70, p<0.05), SLC39A14 (ICM, FC=-1.97, p<0.05) and SLC39A8(ICM, FC=-1.60, p<0.05; DCM, FC=-1.78, p<0.01). Myoglobin was increased (FC=1.18, p<0.05) and its miRNA, miR-133a-3p, decreased (FC=-1.39, p<0.05) in DCM patients. While other molecules implicated in iron metabolism such as NFE2L2 (ICM, FC=-1.52; DCM, FC=-1.30; p<0.05) and AGPAT5 (ICM, FC=-1.84, p<0.05) are decreased. It is worth noting the correlation with ventricular dysfunction shown by SLC39A8 (end systolic diameter, r=-0.674; end diastolic diameter, r=-0.648; p<0.05) in ICM patients and NFE2L2 (ejection fraction, r=0.609, p<0.05) in DCM patients. Conclusions Our results show an alteration in the iron metabolism specific of aetiology in HF, both in the genes involved in different functions of the pathway and in its post-translational regulation. These results offer new possible therapeutic targets and valuable information to elucidate the complex mechanisms that relate iron homeostasis to HF.