Single high-dose intramyocardial administration of erythropoietin promotes early intracardiac proliferation, proves safety and restores cardiac performance after myocardial infarction in rats.
Various studies demonstrate erythropoietin (EPO) as a cardioprotective growth hormone. Recent findings reveal EPO in addition might induce proliferation cascades inside myocardium. We aimed to evaluate whether a single high-dose intramyocardial EPO administration safely elevates early intracardiac cell proliferation after myocardial infarction (MI). Following permanent MI in rats EPO (3000 U/kg) in MI EPO-treatment group (n=99) or saline in MI control group (n=95) was injected along the infarction border. Intramyocardial EPO injection activated the genes of cyclin D1 and cell division cycle 2 kinase (cdc2) at 24 h after MI (n=6, P<0.05) evaluated by real time-PCR. The number of Ki-67+ intracardiac cells analyzed following immunohistochemistry was significantly enhanced by 45% in the peri-infarction zone at 48 h after EPO treatment (n=6, P<0.001). Capillary density was significantly enhanced by 17% as early as seven days (n=6, P<0.001). After six weeks, left ventricular performance assessed by conductance catheters was restored under baseline and dobutamine induced stress conditions (n=11-14, P<0.05). No thrombus formation was observed in the heart and in distant organs. No deleterious systemic adverse effects were apparent. Single high-dose intramyocardial EPO delivery proved safety and promoted early intracardiac cell proliferation, which might in part have contributed to an attenuated myocardial functional decline.
Gäbel
Ralf
R
Department of Cardiac Surgery, University of Rostock, Germany.
Klopsch
Christian
C
Furlani
Dario
D
Yerebakan
Can
C
Li
Wenzhong
W
Ugurlucan
Murat
M
Ma
Nan
N
Steinhoff
Gustav
G
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage*; D015552:Injections, Intralesional; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
D002316:Cardiotonic Agents; C530106:Ccnd1 protein, rat; D019394:Ki-67 Antigen; D004921:Erythropoietin; D019938:Cyclin D1; D016203:CDC2 Protein Kinase