Original ArticleShort- and Long-Term Cardioprotective Effect of Darbepoetin-α: Role of Bcl-2 Family ProteinsSchlecht-Bauer, Déborah PhD*‡; Antier, Daniel PharmD, PhD*; Machet, Marie-Christine PhD†; Hyvelin, Jean-Marc PhD*‡Author Information From the *Laboratoire de Physiopathologie de la Paroi Artérielle, Faculté de Médecine, Tours, France; †Service d'Anatomie et Cytologie Pathologique, Hôpital Trousseau, Tours, France; and ‡Both authors contributed equally to this work. Received for publication March 18, 2009; accepted May 21, 2009. The authors report no conflicts of interest. Reprints: Déborah Schlecht-Bauer, PharmD, PhD, LABPART, EA3852, IFR 135, Faculté de Médecine, 10 Bd Tonnellé, 37032 Tours Cedex, France (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: September 2009 - Volume 54 - Issue 3 - p 223-231 doi: 10.1097/FJC.0b013e3181b04d01 Buy Metrics Abstract The purpose of this study was to assess the short- and long-term cardioprotective effects of darbepoetin-α (DA) in a rat myocardial ischemia and reperfusion model and to investigate the signaling pathway through which DA limits cardiomyocytes apoptosis. Rats were subjected to 40 minutes of coronary artery ligation followed by 72 hours or 4 weeks reperfusion and received either DA (3 or 30 μg/kg, DA3 and D30 groups) or vehicle (control) prior to ischemia. In the DA groups reperfused for 72 hours, left ventricular shortening fraction and left ventricular ejection fraction were higher than that in the control rats (P < 0.05), in agreement with a smaller left ventricular (LV) infarct size. DA treatment activated the JAK2/Akt signaling pathway, lowered cleaved caspase-3, and increased both phosphorylated-Bad and phosphorylated-GSK-3β proteins. This was consistent with the decrease of reactive oxygen species production and the lowered binding of Bad to Bcl-xL and Bcl-2 in a DA30 group of rats. Similarly, in the DA-4-week group, LV function was greater compared to the control. Histology alterations implicated lower LV cardiac fibrosis and greater capillary density; furthermore, both Bcl-xL and Bcl-2 were upregulated. In conclusion, DA afforded short- and long-term cardioprotective effects. Antiapoptotic effects, through the activation of Akt that regulates the Bcl-2 family proteins and activates GSK-3β, are central in the DA cardioprotective mechanism. © 2009 Lippincott Williams & Wilkins, Inc.