Reduction of myocardial damage during acute ischemia

减少急性缺血期间的心肌损伤

• 批准号: 7732335
• 负责人: Mark Talan
• 金额: $ 7.59万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732335
• 关键词: Acute; Acute myocardial infarction; Anemia; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Area; Attenuated; Blood Circulation; Cardiac; Cell Survival; Cells; Cessation of life; Chronic; Consensus; Coronary; Coronary artery; Daily; Developed Countries; Development; Dose; Effectiveness; Elderly; Erythropoiesis; Erythropoietin; Goals; Heart; Heart failure; Hour; Infarction; Injection of therapeutic agent; Intravenous; Ischemia; Left Ventricular Remodeling; Ligation; Measures; Modality; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Phase; Property; Rate; Rattus; Risk; Severities; Site; Therapeutic; Tissues; United States Food and Drug Administration; Week; functional decline; in vivo; mortality; myocardial infarct sizing; pre-clinical; prevent; programs; recombinant human erythropoietin; research study; restoration; success; translational study

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.

该项目的主要目标是在心肌缺血动物模型上进行临床前实验，以阐明心肌细胞死亡和随后 CHF 发展的机制，并评估不同治疗方式的潜力。最终目标是限制心肌损伤的程度并预防或减轻 CHF 的发展。 促红细胞生成素减轻心肌缺血损伤。 促红细胞生成素（EPO）是红细胞生成的天然兴奋剂，最近成为具有神经保护特性的潜在抗凋亡因子。我们已经证明 EPO 的抗细胞凋亡作用还具有心脏保护作用。在大鼠实验中，我们发现，在冠状动脉永久结扎后立即全身注射重组人 EPO（3000 IU/kg），八周后心肌梗塞面积可减少 75%。在诱导心肌梗塞后八周内，EPO治疗大鼠的左心室重塑和功能下降显着减弱，并且与假手术动物在统计学上没有差异。冠状动脉结扎后24小时，与未治疗的动物相比，在EPO治疗的大鼠中，在心肌危险区域（紧邻梗塞部位的区域）测得的凋亡肌细胞的数量减少了一半。在随后的实验中，我们确定单次静脉注射剂量 3000 IU/kg 在冠状动脉结扎后 12 小时内具有心脏保护作用，但在 24 小时后就失去了心脏保护作用。如果动物在冠状动脉结扎后立即使用EPO治疗，则治疗剂量可减少至150 IU/kg（通常，FDA批准的治疗贫血的剂量），而不会失去有效性，但是，在这种情况下，治疗窗口也减少至4小时。 在其他实验中，我们表明，与冠状连接后立即注射一次相比，每天重复注射 EPO 没有任何额外的好处。