Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 293; no. 1; pp. H60 - H68
• Main Authors: Gao, Erhe, Boucher, Matthieu, Chuprun, J. Kurt, Zhou, Rui-Hai, Eckhart, Andrea D, Koch, Walter J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2007
• Subjects: Animals; Apoptosis; Cardiotonic Agents - administration & dosage; Cardiovascular disease; Darbepoetin alfa; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin - administration & dosage; Erythropoietin - analogs & derivatives; Heart attacks; Hematinics - administration & dosage; Humans; Hypoxia; Male; Myocardial Ischemia - diagnosis; Myocardial Ischemia - drug therapy; Myocardial Ischemia - physiopathology; Rats; Rats, Sprague-Dawley; Rodents; Treatment Outcome
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00227.2007

1 George Zallie and Family Laboratory for Cardiovascular Gene Therapy and 2 Eugene Feiner Laboratory for Vascular Biology and Thrombosis, Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania Submitted 21 February 2007 ; accepted in final form 20 March 2007 Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog darbepoetin alfa (DA) in a rat model of ischemia-reperfusion (I/R) injury. Rats were subjected to 30-min ischemia followed by 72-h reperfusion. In a dose-response study, DA (2, 7, 11, and 30 µg/kg) or vehicle was administered as a single bolus at the start of ischemia. To determine the time window of potential cardioprotection, a single high dose of DA (30 µg/kg) was given at either the initiation or the end of ischemia or at 1 or 24 h after reperfusion. After 3 days, cardiac function and infarct size were assessed. Acute myocyte apoptosis was quantified by TUNEL staining on myocardial sections and by caspase-3 activity assays. DA significantly reduced infarct size from 32.8 ± 3.5% (vehicle) to 11.0 ± 3.3% in a dose-dependent manner, while there was no difference in ischemic area between groups. Treatment with DA as late as 24 h after the beginning of reperfusion still demonstrated a significant reduction in infarct size (17.0 ± 1.6%). Consistent with infarction data, DA improved in vivo cardiac reserve compared with vehicle. Finally, DA significantly decreased myocyte apoptosis and caspase-3 activity after I/R. These data indicate that DA protects the heart against I/R injury and improves cardiac function, apparently through a reduction of myocyte apoptosis. Of clinical importance pointing toward a relevant therapeutic utility, we report that even if given 24 h after I/R injury, DA can significantly protect the myocardium. myocardial ischemia; ischemia-reperfusion injury; apoptosis Address for reprint requests and other correspondence: W. J. Koch, Center for Translational Medicine, George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Thomas Jefferson Univ., 1025 Walnut St., Rm. 317, Philadelphia, PA 19107 (e-mail: walter.koch{at}jefferson.edu )