Parsa Cyrus J, Kim Jihee, Riel Ryan U, Pascal Laura S, Thompson Richard B, Petrofski Jason A, Matsumoto Akio, Stamler Jonathan S, Koch Walter J
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Biol Chem. 2004 May 14;279(20):20655-62. doi: 10.1074/jbc.M314099200. Epub 2004 Mar 11.
Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this study, we evaluated the in vivo protective potential of erythropoietin in the reperfused rabbit heart following ventricular ischemia. We show that "preconditioning" with erythropoietin activates cell survival pathways in myocardial tissue in vivo and adult rabbit cardiac fibroblasts in vitro. These pathways, activated by erythropoietin in both whole hearts and cardiac fibroblasts, are also activated acutely by ischemia/reperfusion injury. Moreover, in vivo studies indicate that erythropoietin treatment either prior to or during ischemia significantly enhances cardiac function and recovery, including left ventricular contractility, following myocardial ischemia/reperfusion. Our data indicate that a contributing in vivo cellular mechanism of this protection is mitigation of myocardial cell apoptosis. This results in decreased infarct size as evidenced by area at risk studies following in vivo ischemia/reperfusion injury, translating into more viable myocardium and less ventricular dysfunction. Therefore, erythropoietin treatment may offer novel protection against ischemic heart disease and may act, at least in part, by direct action on cardiac fibroblasts and myocytes to alter survival and ventricular remodeling.
最近研究表明，促红细胞生成素除了具有造血作用外，还有其他作用，比如预防继发于缺血的神经元和心肌细胞凋亡。在本研究中，我们评估了促红细胞生成素对兔心室缺血再灌注心脏的体内保护潜力。我们发现，促红细胞生成素“预处理”可在体内激活心肌组织中的细胞存活通路，并在体外激活成年兔心脏成纤维细胞中的细胞存活通路。促红细胞生成素在整个心脏和心脏成纤维细胞中激活的这些通路，也会被缺血/再灌注损伤急性激活。此外，体内研究表明，在缺血之前或期间给予促红细胞生成素治疗，可显著增强心肌缺血/再灌注后的心脏功能及恢复情况，包括左心室收缩力。我们的数据表明，这种保护作用在体内的细胞机制之一是减轻心肌细胞凋亡。这导致梗死面积减小，体内缺血/再灌注损伤后的危险区域研究证明了这一点，意味着有更多存活的心肌组织和更少的心室功能障碍。因此，促红细胞生成素治疗可能为缺血性心脏病提供新的保护作用，并且至少部分是通过直接作用于心脏成纤维细胞和心肌细胞来改变细胞存活及心室重塑。
