Department of Medicine, University of Verona and AOUI Verona, Verona.
Iron Research Laboratory, Lindsley Kimball Research Institute, New York Blood Center, New York, NY, USA; Dept. of Pathology and Laboratory Medicine, Weill Cornell Medicine.
Haematologica. 2023 May 1;108(5):1335-1348. doi: 10.3324/haematol.2022.281995.
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.
肥厚型心肌病严重影响β-地中海贫血或输血依赖型骨髓增生异常综合征患者的生活质量和死亡率。最近，在肝铁过载的小鼠模型中已经报道了 Nrf2 活性与铁代谢之间的联系。在这里，我们研究了 C57B6 小鼠作为健康对照和核红细胞因子-2 敲除（Nrf2-/-）雄性小鼠，年龄分别为 4 个月和 12 个月。11 个月大的野生型和 Nrf2-/-小鼠分别用标准饮食或含有 2.5%羰基铁（铁过载[IO]）的饮食喂养 4 周。我们表明，Nrf2-/-小鼠会发生年龄依赖性的心肌病，其特征是严重的氧化、SERCA2A 降解和铁积累。这与局部铁调素表达和血清中非转铁蛋白结合铁增加有关，后者促进了转化生长因子-β（TGF-β）途径的过度激活导致的心脏重塑和间质纤维化。当小鼠暴露于 IO 饮食时，Nrf2 的缺失反而对进一步的心脏铁积累具有保护作用。事实上，氧化的延长和 IO 饮食引起的爆发相结合导致未折叠蛋白反应（UPR）系统的激活，该系统反过来独立于心脏铁积累促进铁调素表达。在 Hbbth3/+ 小鼠的心脏中，一种中间型β-地中海贫血的模型，尽管 Nrf2 途径被激活，但我们发现严重的蛋白质氧化、UPR 系统的激活和心脏纤维化独立于心脏铁含量。我们描述了 Nrf2 在衰老与 IO 结合时的双重作用及其与 UPR 系统的新关联，以确保细胞存活。我们为在出现心脏铁积累之前，对中间型β-地中海贫血患者的心肌病进行早期和强化治疗开辟了新的前景。
