Dysregulation of Iron Metabolism-Linked Genes at Myocardial Tissue and Cell Levels in Dilated Cardiomyopathy

Abstract

In heart failure, the biological and clinical connection between abnormal iron homeostasis, myocardial function, and prognosis is known; however, the expression profiles of iron-linked genes both at myocardial tissue and single-cell level are not well defined. Through publicly available bulk and single-nucleus RNA sequencing (RNA-seq) datasets of left ventricle samples from adult non-failed (NF) and dilated cardiomyopathy (DCM) subjects, we aim to evaluate the altered iron metabolism in a diseased condition, at the whole cardiac tissue and single-cell level. From the bulk RNA-seq data, we found 223 iron-linked genes expressed at the myocardial tissue level and 44 differentially expressed between DCM and NF subjects. At the single-cell level, at least 18 iron-linked expressed genes were significantly regulated in DCM when compared to NF subjects. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels, including: (1) imbalance of Fe³⁺ internalization (<i>SCARA5</i> down-regulation) and reduction of internal conversion from Fe³⁺ to Fe²⁺ (<i>STEAP3</i> down-regulation), (2) increase of iron consumption to produce hemoglobin (<i>HBA1/2</i> up-regulation), (3) higher heme synthesis and externalization (<i>ALAS2</i> and <i>ABCG2</i> up-regulation), (4) lower cleavage of heme to Fe²⁺, biliverdin and carbon monoxide (<i>HMOX2</i> down-regulation), and (5) positive regulation of hepcidin (<i>BMP6</i> up-regulation).