Reduction of myocardial damage during acute ischemia

该项目的主要目的是对心肌缺血动物模型进行临床前实验，以阐明心肌细胞死亡的机制和随后CHF的发展，并评估不同治疗方式的潜力。最终目的是限制心肌损伤的程度，预防或减轻CHF的发展。 促红细胞生成素可减轻心肌缺血性损伤。 促红细胞生成素（EPO）是一种天然的促红细胞生成素，具有神经保护作用。我们已经证明，EPO的抗凋亡作用也导致心脏保护。在大鼠的实验中，我们表明，在冠状动脉永久结扎后立即单次全身给予重组人EPO（3000 IU/kg），8周后心肌梗死面积减少75%。在诱导心肌梗死后8周内，EPO治疗组大鼠的左室重构和功能下降明显减轻，与假手术组相比无统计学差异。在冠状动脉结扎后24小时，在心肌危险区（紧邻梗塞部位的区域）中测量的凋亡心肌细胞的量与未处理的动物相比在EPO处理的大鼠中减少一半。在随后的实验中，我们确定了3000 IU/kg的单次静脉内剂量在冠状动脉结扎后长达12小时具有心脏保护作用，但在24小时后失去其心脏保护特性。如果在冠状动脉结扎后立即用EPO治疗动物，则治疗剂量可以减少至150 IU/kg（通常，FDA批准的用于治疗贫血的剂量）而不丧失有效性，然而，在这种情况下的治疗窗也减少至4小时。 在另外的实验中，我们表明，与冠状动脉结扎后立即单次注射相比，每天重复注射EPO没有任何额外的益处。

The broad objective of this program is to perform preclinical experimentation on animal models of myocardial ischemia to elucidate the mechanisms of cellular death in the myocardium and development of the subsequent CHF and to evaluate the potential of different therapeutic modalities. The ultimate goal is to limit the extent of myocardial damage and to prevent or attenuate the development of CHF. Erythropoietin reduses the myocardial ischemic damage. Erythropoietin (EPO), natural stimulant of erythropoiesis, recently emerged as potential antiapoptotic factor with neuroprotective properties. We have demonstrated that the antiapoptotic effects of EPO also resulted in cardioprotection. In experiments in rats we showed that single systemic administration of recombinant human EPO (3000 IU/kg) immediately after permanent ligation of a coronary artery results in 75% reduction of the size of myocardial infarction eight weeks later. During eight weeks after induction of myocardial infarction, left ventricular remodeling and function decline in EPO treated rats was significantly attenuated and statistically was not different from that in sham operated animals. Twenty four hours after ligation of coronary artery the amount of apoptotic myocytes measured in the myocardial risk area (area immediately adjacent to the infarct site) was reduced in half in the EPO treated rats in comparison to untreated animals. In subsequent experiments we established that single intravenous dose of 3000 IU/kg is cardioprotective up to 12 hrs after coronary ligation, but it is losing its cardioprotective properties after 24 hrs. If animals are treated with EPO immediately after coronary ligation, the treatment dose can be reduced up to 150 IU/kg (usual, FDA approved dose for the treatment of anemia) without the lose of effectiveness, however, the therapeutic window in this case is also reduced to 4 hrs. In additional experiments we showed that repeated daily EPO injection do not have any added benefits comparing with a single injection immediately after coronaty ligation.