Duality of Nrf2 in iron-overload cardiomyopathy

: Cardiomyopathy deeply affects quality of life and mortality of patients with β-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 as healthy control and Nrf2-/- male mice aged 4- and 12-months.11-months old wild-type (WT) and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (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 NTBI, which promotes a maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of TGF-β 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 UPR system, which in turn promotes hepcidin expression independently from heart iron accumulation. In heart from Hbbth3/+ mice, a model of mmthalassemia 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 ironoverload and its novel interrelation with UPR system to ensure cell survival. We open new perspective for early and intense treatment of cardiomyopathy in patients with β- thalassemia before the appearance of heart iron accumulation.