Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia
Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia
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DOI：
10.1093/cvr/cvt010
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发表时间：
2013-04-01
影响因子：
10.8
通讯作者：
de Boer, Rudolf A.
中科院分区：
文献类型：
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作者：
Mahmud, Hasan;Ruifrok, Willem P. T.;de Boer, Rudolf A.
红细胞自杀性死亡的特征是细胞萎缩和磷脂酰丝氨酸(PS)残基暴露在细胞表面。过度的胰酶消化可能会导致贫血。我们的目的是研究胰酶在心力衰竭相关贫血中的作用。我们在心力衰竭的啮齿动物模型中测量了胰酶活性。用流式细胞仪检测PS暴露、细胞内钙离子水平升高和细胞体积减小等典型的细胞复苏指标。转基因REN2大鼠表现出轻度贫血，与SD对照组大鼠相比，红细胞PS暴露增加了两倍(P0.01)。在氧化应激、高渗休克和能量耗竭等催眠因素的刺激下，REN2的催眠作用更为明显，表现为PS暴露增加、胞浆钙内流和细胞收缩(P005vs.SD)。胞内Ca-2水平的升高导致REN2红细胞PS暴露的增加(P0.01与SD相比)。因此，抑制Ca-2进入可以钝化氧化应激下PS暴露的增加。REN2大鼠的网织红细胞显著增加(REN2：10.6 2.3；SD：5.4 0.1；P<0.05)，红细胞转换率增加，表现为红细胞清除率增加。在高血压心脏重塑的大鼠模型(单肾切除的大鼠植入了脱氧皮质酮醋酸酯颗粒)中，在横状主动脉收缩后的小鼠中，以及在人类心力衰竭患者中的一项小型验证性研究中，心力衰竭患者的心功能也增加了。在心力衰竭的发展过程中，心力衰竭的心功能会增加，并可能导致心力衰竭相关的贫血。因此，Eyptosis可能成为治疗HF相关性贫血的新靶点。
Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage and exposure of phosphatidylserine (PS) residues at the cell surface. Excessive eryptosis may lead to anaemia. We aimed to study the role of eryptosis in heart failure (HF)-associated anaemia.We measured eryptosis in rodent models of HF. Typical measures of eryptosis including PS-exposure, increased intracellular Ca-2 levels, and decreased cell volume were determined by flow cytometry. Transgenic REN2 rats displayed mild anaemia which was associated with a two-fold increase in erythrocyte PS-exposure when compared with Sprague Dawley (SD) control rats (P 0.01). Upon stimulation with eryptotic triggers such as oxidative stress, hyperosmotic shock and energy depletion, eryptosis was more prominent in REN2 as shown by increased PS-exposure, cytosolic Ca-2 influx, and cell shrinkage (P 0.05 vs. SD). Increasing cytosolic Ca-2 levels resulted in a stronger increase in PS-exposure in REN2 erythrocytes (P 0.01 vs. SD). Accordingly, inhibition of Ca-2 entry blunted the increased PS-exposure upon oxidative stress. The REN2 rats had significantly higher reticulocytes (REN2: 10.6 2.3; SD: 5.4 0.1; P 0.05) and erythrocyte turnover was increased, indicated by increased clearance of eryptotic erythrocytes. Eryptosis was also increased in a rat model of hypertensive cardiac remodelling (uninephrectomized rats implanted with deoxycorticosterone acetate pellets), in mice after transverse aortic constriction, as well as in a small proof-of-concept study in human HF patients.Eryptosis is increased during HF development and could contribute to HF-associated anaemia. Eryptosis may therefore become a novel target for therapy in HF-associated anaemia.