Short- and long-term cardioprotective effect of darbepoetin-alpha: role of Bcl-2 family proteins.
The purpose of this study was to assess the short- and long-term cardioprotective effects of darbepoetin-alpha (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 microg/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-3beta 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-3beta, are central in the DA cardioprotective mechanism.
Schlecht-Bauer
Déborah
D
Laboratoire de Physiopathologie de la Paroi Artérielle, Faculté de Médecine, Tours, France. dschlecht@hotmail.fr
Antier
Daniel
D
Machet
Marie-Christine
MC
Hyvelin
Jean-Marc
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D000068256:Darbepoetin alfa; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors
D002316:Cardiotonic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3