Hamed Saher, Barshack Iris, Luboshits Galia, Wexler Dov, Deutsch Varda, Keren Gad, George Jacob
Department of Cardiology, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Israel.
Eur Heart J. 2006 Aug;27(15):1876-83. doi: 10.1093/eurheartj/ehl044. Epub 2006 May 26.
Doxorubicin (Dox) is a potent chemotherapeutic agent associated with severe cardiotoxicity. Erythropoietin (Epo) has recently been shown to exhibit proangiogenic properties related to endothelial progenitor cell (EPC) mobilization. We tested the hypothesis that EPC are compromised in rats with Dox-induced cardiotoxicity and correction of this functional impairment by treatment with Epo could result in attenuation of myocardial dysfunction.
Wistar rats were either treated with two different doses of Epo (20U or 200U) or PBS (n = 40 in each group) for four consecutive weeks, followed by Dox administration. In a second study, EPC obtained from healthy rats were transfused intravenously (n = 20/group) prior to induction of Dox cardiomyopathy. EPC from healthy subjects were evaluated for their proliferative and migratory properties in the presence or absence of Dox and Epo pre-treatment. Echocardiography demonstrated an improvement in fractional shortening (FS) in Epo-treated rats. Epo treatment was associated with a reduced mortality in both Epo-treated groups. Circulating EPC numbers were three times higher in Epo-treated compared with non-treated animals. Adhesive properties, migration, and tube formation capacity in matrigel of EPCs from both Epo-treated groups as compared with controls were significantly enhanced. EPC transfer to Dox-treated rats led to functional myocardial improvement equivalent to the protection afforded by treatment with Epo. In EPC obtained from humans, pre-incubation with Epo significantly attenuated the anti-proliferative and anti-migratory effects of treatment with Dox.
Epo treatment is potentially protective against myocardial dysfunction induced by Dox. These effects are partially mediated by enhancement in the number of EPC and their functional properties.
阿霉素（Dox）是一种强效化疗药物，与严重的心脏毒性相关。促红细胞生成素（Epo）最近被证明具有与内皮祖细胞（EPC）动员相关的促血管生成特性。我们检验了这样一个假设，即Dox诱导的心脏毒性大鼠的EPC受损，用Epo治疗纠正这种功能障碍可导致心肌功能障碍减轻。
将Wistar大鼠连续四周用两种不同剂量的Epo（20U或200U）或PBS（每组n = 40）治疗，随后给予Dox。在第二项研究中，在诱导Dox心肌病之前，将从健康大鼠获得的EPC静脉输注（每组n = 20）。评估健康受试者的EPC在有或没有Dox和Epo预处理的情况下的增殖和迁移特性。超声心动图显示Epo治疗的大鼠的缩短分数（FS）有所改善。Epo治疗与两个Epo治疗组的死亡率降低相关。与未治疗的动物相比，Epo治疗组的循环EPC数量高出三倍。与对照组相比，两个Epo治疗组的EPC在基质胶中的黏附特性、迁移和管形成能力均显著增强。将EPC转移至Dox治疗的大鼠导致心肌功能改善，相当于Epo治疗所提供的保护。在从人类获得的EPC中，用Epo预孵育可显著减弱Dox治疗的抗增殖和抗迁移作用。
Epo治疗可能对Dox诱导的心肌功能障碍具有保护作用。这些作用部分是由EPC数量及其功能特性的增强介导的。
