title: Single high-dose intramyocardial administration of erythropoietin promotes early intracardiac proliferation, proves safety and restores cardiac performance after myocardial infarction in rats.
abstract: 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.
authors.affiliation: Department of Cardiac Surgery, University of Rostock, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gäbel
authors.forename: Christian
authors.initials: C
authors.lastname: Klopsch
authors.forename: Dario
authors.initials: D
authors.lastname: Furlani
authors.forename: Can
authors.initials: C
authors.lastname: Yerebakan
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Li
authors.forename: Murat
authors.initials: M
authors.lastname: Ugurlucan
authors.forename: Nan
authors.initials: N
authors.lastname: Ma
authors.forename: Gustav
authors.initials: G
authors.lastname: Steinhoff
mesh_terms: 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*
chemical_list: D002316:Cardiotonic Agents; C530106:Ccnd1 protein, rat; D019394:Ki-67 Antigen; D004921:Erythropoietin; D019938:Cyclin D1; D016203:CDC2 Protein Kinase