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

settings Order Article Reprints Open AccessArticle Dysregulation of Iron Metabolism-Linked Genes at Myocardial Tissue and Cell Levels in Dilated Cardiomyopathy by Ilaria Massaiu 1,†, Jeness Campodonico 1,†, Massimo Mapelli 1 [ORCID] , Elisabetta Salvioni 1, Vincenza Valerio 1, Donato Moschetta 1,2 [ORCID] , Veronika A. Myasoedova 1 [ORCID] , Maria Domenica Cappellini 3,4 [ORCID] , Giulio Pompilio 1,5, Paolo Poggio 1,*,‡ [ORCID] and Piergiuseppe Agostoni 1,4,*,‡ 1 Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy 2 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20122 Milan, Italy 3 UOC General Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy 4 Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy 5 Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy * Authors to whom correspondence should be addressed. † These authors equally contributed as first author. ‡ These authors equally contributed as last author. Int. J. Mol. Sci. 2023, 24(3), 2887; https://doi.org/10.3390/ijms24032887 Received: 23 December 2022 / Revised: 19 January 2023 / Accepted: 26 January 2023 / Published: 2 February 2023 (This article belongs to the Special Issue Iron Metabolism in Health and Disease) Download Browse Figures Versions Notes 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 (SCARA5 down-regulation) and reduction of internal conversion from Fe3+ to Fe2+ (STEAP3 down-regulation), (2) increase of iron consumption to produce hemoglobin (HBA1/2 up-regulation), (3) higher heme synthesis and externalization (ALAS2 and ABCG2 up-regulation), (4) lower cleavage of heme to Fe2+, biliverdin and carbon monoxide (HMOX2 down-regulation), and (5) positive regulation of hepcidin (BMP6 up-regulation).