title: Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart.
abstract: 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 mug/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 mug/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.
authors: Center for Translational Medicine, George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA.
authors: Erhe
authors: E
authors: Gao
authors: Matthieu
authors: M
authors: Boucher
authors: J Kurt
authors: JK
authors: Chuprun
authors: Rui-Hai
authors: RH
authors: Zhou
authors: Andrea D
authors: AD
authors: Eckhart
authors: Walter J
authors: WJ
authors: Koch
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006397:Hematinics / Q000008:administration & dosage; D006801:Humans; D008297:Male; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D002316:Cardiotonic Agents; D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa