Naito Yoshiro, Sawada Hisashi, Oboshi Makiko, Iwasaku Toshihiro, Okuhara Yoshitaka, Morisawa Daisuke, Eguchi Akiyo, Hirotani Shinichi, Mano Toshiaki, Tsujino Takeshi, Masuyama Tohru
aCardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya bDepartment of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
J Hypertens. 2015 Jun;33(6):1267-75. doi: 10.1097/HJH.0000000000000547.
Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency.
Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated.
Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency.
These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.
贫血是心力衰竭患者常见的合并症，铁缺乏是已知的心力衰竭患者贫血的原因之一。最近的研究表明，单纯铁缺乏而无明显贫血与心力衰竭患者的不良预后相关。因此，为了将心力衰竭患者的死亡率降至最低，了解铁缺乏与心脏功能之间的联系很重要。慢性未经治疗的铁缺乏会导致心脏重塑，我们之前曾报道促红细胞生成素（Epo）和心脏Epo受体（EpoR）信号传导可能与其重塑有关。然而，EpoR信号传导与其重塑之间的联系仍有待阐明。在此，我们研究了EpoR信号传导在慢性铁缺乏反应中对心脏重塑的作用。
野生型小鼠和仅在造血谱系中表达EpoR的转基因拯救EpoR基因敲除突变小鼠（EpoR限制小鼠），分别给予正常饮食或缺铁饮食，并研究其分子机制。
饮食铁限制逐渐导致野生型小鼠贫血、Epo分泌和心脏肥大。相比之下，与野生型小鼠相比，缺铁饮食喂养的EpoR限制小鼠表现出贫血、左心室扩张和心脏功能障碍。有趣的是，铁缺乏后在EpoR限制小鼠中观察到心脏线粒体生物发生改变。此外，与野生型小鼠相比，铁缺乏后EpoR限制小鼠的心脏p53表达增加。
这些数据表明，EpoR信号传导与慢性铁缺乏后的心脏重塑有关。
