Department of Medicine, University of Verona and AOUI Verona, Verona
Francesca Vinchi
Iron Research Laboratory, Lindsley Kimball Research Institute, New York Blood Center, New York, NY, USA; Dept. of Pathology and Laboratory Medicine, Weill Cornell Medicine
Iana Iatcenko
Department of Medicine, University of Verona and AOUI Verona, Verona
Alessandra Ghigo
Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarrone”, University of Torino, Torino
Alessandro Matte
Department of Medicine, University of Verona and AOUI Verona, Verona
Serge Cedrick Mbiandjeu Toya
Department of Medicine, University of Verona and AOUI Verona, Verona
Angela Siciliano
Department of Medicine, University of Verona and AOUI Verona, Verona
Deborah Chiabrando
Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarrone”, University of Torino, Torino
Emanuela Tolosano
Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarrone”, University of Torino, Torino
Steven Zebulon Vance
Iron Research Laboratory, Lindsley Kimball Research Institute, New York Blood Center, New York, NY
Veronica Riccardi
Department of Medicine, University of Verona and AOUI Verona, Verona
Immacolata Andolfo
Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples; CEINGE - Biotecnologie Avanzate, Naples
Manuela Iezzi
Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti, Chieti
Alessia Lamolinara
Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti, Chieti
Achille Iolascon
Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples; CEINGE - Biotecnologie Avanzate, Naples
Lucia De Franceschi
Department of Medicine, University of Verona and AOUI Verona, Verona
Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.
